Multi-directional deflectable catheter apparatuses, systems, and methods for renal neuromodulation

ABSTRACT

Multi-directional deflectable catheter apparatuses, systems, and methods for achieving renal neuromodulation by intravascular access are disclosed herein. One aspect of the present application, for example, is directed to apparatuses, systems, and methods that incorporate a catheter treatment device comprising an elongated shaft. The elongated shaft is sized and configured to deliver a thermal element to a renal artery via an intravascular path. Thermally or electrical renal neuromodulation may be achieved via direct and/or via indirect application of thermal and/or electrical energy to heat or cool, or otherwise electrically modulate, neural fibers that contribute to renal function, or of vascular structures that feed or perfuse the neural fibers.

REFERENCE TO RELATED APPLICATION(S)

The present application is a continuation of U.S. patent applicationSer. No. 12/871,457, filed Aug. 30, 2010, now U.S. Pat. No. 8,728,075,which claims the benefit of U.S. Provisional Patent Application No.61/328,105, filed on Apr. 26, 2010, and the disclosures of which areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The technologies disclosed in the present application generally relateto catheter apparatuses, systems and methods for intravascularneuromodulation. More particularly, the technologies disclosed hereinrelate to multi-directional deflectable catheter apparatuses, systems,and methods for achieving intravascular renal neuromodulation viaapplication of thermal and/or electrical energy.

BACKGROUND

Hypertension, heart failure, chronic kidney disease, insulin resistance,diabetes and metabolic syndrome represent a significant and growingglobal health issue. Current therapies for these conditions includenon-pharmacological, pharmacological and device-based approaches.Despite this variety of treatment options, the rates of control of bloodpressure and the therapeutic efforts to prevent progression of thesedisease states and their sequelae remain unsatisfactory. Although thereasons for this situation are manifold and include issues ofnon-compliance with prescribed therapy, heterogeneity in responses bothin terms of efficacy and adverse event profile, and others, it isevident that alternative options are required to supplement the currenttherapeutic treatment regimes for these conditions.

Reduction of sympathetic renal nerve activity (e.g., via denervation),can reverse these processes. Ardian, Inc., of Palo Alto, Calif., hasdiscovered that an energy field, including and comprising an electricfield, can initiate renal neuromodulation via denervation caused byirreversible electroporation, electrofusion, apoptosis, necrosis,ablation, thermal alteration, alteration of gene expression or anothersuitable modality.

Catheter-based intervention is widely used for medical treatments whereaccess to a location in the body is obtained, for example, through avessel of the cardiovascular system. Ardian, Inc. has shown that anenergy field can be applied to the sympathetic renal nerves from withina renal artery. The renal artery has features unique from other vesselsor parts of the body and thus applying an energy field to thesympathetic renal nerves from within the renal artery is not trivial.Accordingly, a need exists for a catheter capable of effectivelydelivering energy to the renal sympathetic nerves from within a renalartery, where the catheter is better configured to i) navigate through arenal artery with reduced risk of applying traumatic force to the arterywall; ii) precisely place an energy delivery element at a desiredlocation on the vessel wall; and iii) maintain stable contact betweenthe energy delivery element and the location on the vessel wall duringblood flow pulsatility and respiratory motion of the renal artery.

SUMMARY

The following summary is provided for the benefit of the reader only,and is not intended to limit the disclosure in any way. The presentapplication provides catheter apparatuses, systems and methods forachieving electrically- and/or thermally-induced renal neuromodulationby intravascular access.

One aspect of the present application provides apparatuses, systems, andmethods that incorporate a catheter treatment device comprising anelongated shaft. The elongated shaft is sized and configured to deliverat least one thermal heating element to a renal artery via anintravascular path that includes a femoral artery, an iliac artery andthe aorta. Different sections of the elongated shaft serve differentmechanical functions when in use. The sections are differentiated interms of their size, configuration, and mechanical properties for (i)percutaneous introduction into a femoral or brachial artery through asmall-diameter access site; (ii) atraumatic passage through the tortuousintravascular path through an iliac artery, into the aorta, and into arespective left/right renal artery, including (iii) accommodatingsignificant flexure at the junction of the left/right renal arteries andaorta to gain entry into the respective left or right renal artery; (iv)accommodating controlled translation, deflection, and/or rotation withinthe respective renal artery to attain proximity to and a desiredalignment with an interior wall of the respective renal artery; (v)allowing the placement of at least one thermal heating element intocontact with tissue on the interior wall in an orientation thatoptimizes the active surface area of the thermal heating element; and(vi) allowing substantially stable contact force between the at leastone thermal heating element and the interior wall during motion of therenal artery with respect to the aorta due to respiration and/or bloodflow pulsatility.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 2 is an enlarged anatomic view of nerves innervating a left kidneyto form the renal plexus surrounding the left renal artery.

FIGS. 3A and 3B provide anatomic and conceptual views of a human body,respectively, depicting neural efferent and afferent communicationbetween the brain and kidneys

FIGS. 4A and 4B are, respectively, anatomic views of the arterial andvenous vasculatures of a human.

FIG. 5 is a perspective view of a system for achieving intravascular,thermally-induced renal neuromodulation, comprising a treatment deviceand a generator.

FIGS. 6A to 6C are anatomic views of the intravascular delivery,deflection and placement of various embodiments of the treatment deviceshown in FIG. 5 through the femoral artery and into a renal artery.

FIGS. 7A and 7B are anatomic views of the intravascular delivery,deflection and placement of various embodiments of the treatment deviceshown in FIG. 5 through the femoral artery and into a renal artery.

FIGS. 8A to 8D are a series of views of the elongated shaft of thetreatment device shown in FIG. 5, showing the different mechanical andfunctional regions that the elongated shaft incorporates.

FIG. 8E shows an anatomic view of the placement of the treatment deviceshown in FIG. 5 within the dimensions of the renal artery.

FIGS. 9A to 9C show the placement of a thermal heating element, which iscarried at the distal end of the elongated shaft of the treatment deviceshown in FIG. 5, into contact with tissue along a renal artery.

FIGS. 10A and 10B show placement of the thermal heating element shown inFIGS. 9A to 9C into contact with tissue along a renal artery anddelivery of thermal treatment to the renal plexus.

FIG. 11A shows an open circuit system for actively cooling the thermalheating element and/or the contacted tissue and its surroundings shownin FIGS. 10A and 10B.

FIGS. 11B and 11C are side-sectional and cross-sectional views,respectively, of a closed circuit system for actively cooling thethermal heating element and/or the contacted tissue and its surroundingsshown in FIGS. 10A and 10B.

FIGS. 12A and 12B show a representative embodiment of the forcetransmitting section of the elongated shaft of the treatment deviceshown in FIG. 5.

FIGS. 13A to 13C show a representative embodiment of the proximalflexure zone of the elongated shaft of the treatment device shown inFIG. 5.

FIGS. 14A to 14C show a representative embodiment of the second flexurezone of the elongated shaft of the treatment device shown in FIG. 5.

FIG. 15 shows additional alternative representative embodiments of anelongated shaft for a treatment device like that shown in FIG. 5,showing examples of the different structural, mechanical and functionalregions that the elongated shaft can incorporate.

FIGS. 16A to 16L show additional alternative representative embodimentsof an elongated shaft for a treatment device like that shown in FIG. 5,showing examples of the different structural, mechanical and functionalregions that the elongated shaft can incorporate, wherein the secondflexure zone comprises a centrally positioned spine.

FIGS. 17A to 17B show representative embodiments of handle for atreatment device like that shown in FIG. 5.

FIGS. 18A to 18C show a representative embodiment of the distal flexurezone of the elongated shaft of the treatment device shown in FIG. 5.

FIGS. 18D to 18F show multiple planar views of the bending capability ofthe distal flexure zone corresponding to the elongated shaft of thetreatment device shown in FIG. 5.

FIGS. 18G and 18H show alternative embodiments of the distal flexurezone corresponding to the elongated shaft of the treatment device shownin FIG. 5.

FIGS. 19A and 19B show a representative embodiment of a rotationalcontrol mechanism coupled to the handle assembly of the treatment deviceshown in FIG. 5.

FIGS. 20A to 20C show additional alternative representative embodimentsof an elongated shaft for a treatment device like that shown in FIG. 5,showing examples of the different structural, mechanical and functionalregions that the elongated shaft can incorporate.

FIGS. 21A to 21F show additional alternative representative embodimentsof an elongated shaft for a treatment device like that shown in FIG. 5,showing examples of the different structural, mechanical and functionalregions that the elongated shaft can incorporate.

FIGS. 22A to 22F show additional alternative representative embodimentsof an elongated shaft for a treatment device like that shown in FIG. 5,showing examples of the different structural, mechanical and functionalregions that the elongated shaft can incorporate.

FIGS. 23A to 23E show additional alternative representative embodimentsof an elongated shaft for a treatment device like that shown in FIG. 5,showing examples of the different structural, mechanical and functionalregions that the elongated shaft can incorporate.

FIGS. 24A to 24H show the intravascular delivery, placement, deflection,rotation, retraction, repositioning and use of a treatment device, likethat shown in FIG. 5, to achieve thermally-induced renal neuromodulationfrom within a renal artery.

FIGS. 24I to 24K show the circumferential treatment effect resultingfrom intravascular use of a treatment device, like that shown in FIG. 5.

FIG. 24L shows an alternative intravascular treatment approach using atreatment device, like that shown in FIG. 5.

FIGS. 25A to F show an alternative intravascular treatment approachusing a treatment device, like that shown in FIG. 5.

FIG. 26 shows an energy delivery algorithm corresponding to the energygenerator of a system, like that shown in FIG. 5.

FIG. 27 shows several components of a system and treatment device, likethat shown in FIG. 5, packaged within a single kit.

FIGS. 28A to 28C show fluoroscopic images of a treatment device, likethat shown in FIG. 5, in multiple treatment positions within a renalartery of an animal.

FIGS. 28D and 28E show fluoroscopic images of a treatment device, likethat shown in FIG. 5, in multiple treatment positions within a renalartery during a human study.

DETAILED DESCRIPTION

Although the disclosure hereof is detailed and exact to enable thoseskilled in the art to practice the disclosed technologies, the physicalembodiments herein disclosed merely exemplify the various aspects of theinvention, which may be embodied in other specific structures. While thepreferred embodiment has been described, the details may be changedwithout departing from the invention, which is defined by the claims.

I. PERTINENT ANATOMY AND PHYSIOLOGY

A. The Sympathetic Nervous System

The Sympathetic Nervous System (SNS) is a branch of the autonomicnervous system along with the enteric nervous system and parasympatheticnervous system. It is always active at a basal level (called sympathetictone) and becomes more active during times of stress. Like other partsof the nervous system, the sympathetic nervous system operates through aseries of interconnected neurons. Sympathetic neurons are frequentlyconsidered part of the peripheral nervous system (PNS), although manylie within the central nervous system (CNS). Sympathetic neurons of thespinal cord (which is part of the CNS) communicate with peripheralsympathetic neurons via a series of sympathetic ganglia. Within theganglia, spinal cord sympathetic neurons join peripheral sympatheticneurons through synapses. Spinal cord sympathetic neurons are thereforecalled presynaptic (or preganglionic) neurons, while peripheralsympathetic neurons are called postsynaptic (or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation can elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine and epinephrine bind adrenergic receptorson peripheral tissues. Binding to adrenergic receptors causes a neuronaland hormonal response. The physiologic manifestations include pupildilation, increased heart rate, occasional vomiting, and increased bloodpressure. Increased sweating is also seen due to binding of cholinergicreceptors of the sweat glands.

The sympathetic nervous system is responsible for up- anddown-regulating many homeostatic mechanisms in living organisms. Fibersfrom the SNS innervate tissues in almost every organ system, providingat least some regulatory function to things as diverse as pupildiameter, gut motility, and urinary output. This response is also knownas sympatho-adrenal response of the body, as the preganglionicsympathetic fibers that end in the adrenal medulla (but also all othersympathetic fibers) secrete acetylcholine, which activates the secretionof adrenaline (epinephrine) and to a lesser extent noradrenaline(norepinephrine). Therefore, this response that acts primarily on thecardiovascular system is mediated directly via impulses transmittedthrough the sympathetic nervous system and indirectly via catecholaminessecreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the sympatheticnervous system operated in early organisms to maintain survival as thesympathetic nervous system is responsible for priming the body foraction. One example of this priming is in the moments before waking, inwhich sympathetic outflow spontaneously increases in preparation foraction.

1. The Sympathetic Chain

As shown in FIG. 1, the SNS provides a network of nerves that allows thebrain to communicate with the body. Sympathetic nerves originate insidethe vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors which connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons must travellong distances in the body, and, to accomplish this, many axons relaytheir message to a second cell through synaptic transmission. The endsof the axons link across a space, the synapse, to the dendrites of thesecond cell. The first cell (the presynaptic cell) sends aneurotransmitter across the synaptic cleft where it activates the secondcell (the postsynaptic cell). The message is then carried to the finaldestination.

In the SNS and other components of the peripheral nervous system, thesesynapses are made at sites called ganglia. The cell that sends its fiberis called a preganglionic cell, while the cell whose fiber leaves theganglion is called a postganglionic cell. As mentioned previously, thepreganglionic cells of the SNS are located between the first thoracic(T1) segment and third lumbar (L3) segments of the spinal cord.Postganglionic cells have their cell bodies in the ganglia and sendtheir axons to target organs or glands.

The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Innervation of the Kidneys

As FIG. 2 shows, the kidney is innervated by the renal plexus (RP),which is intimately associated with the renal artery. The renal plexusis an autonomic plexus that surrounds the renal artery and is embeddedwithin the adventitia of the renal artery. The renal plexus extendsalong the renal artery until it arrives at the substance of the kidney.Fibers contributing to the renal plexus arise from the celiac ganglion,the superior mesenteric ganglion, the aorticorenal ganglion and theaortic plexus. The renal plexus (RP), also referred to as the renalnerve, is predominantly comprised of sympathetic components. There is no(or at least very minimal) parasympathetic innervation of the kidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, first lumbar splanchnicnerve, second lumbar splanchnic nerve, and travel to the celiacganglion, the superior mesenteric ganglion, and the aorticorenalganglion. Postganglionic neuronal cell bodies exit the celiac ganglion,the superior mesenteric ganglion, and the aorticorenal ganglion to therenal plexus (RP) and are distributed to the renal vasculature.

3. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages can trigger changes in different parts of the bodysimultaneously. For example, the sympathetic nervous system canaccelerate heart rate; widen bronchial passages; decrease motility(movement) of the large intestine; constrict blood vessels; increaseperistalsis in the esophagus; cause pupil dilation, piloerection (goosebumps) and perspiration (sweating); and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing over-activity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine from the kidneys to plasma revealed increased renalnorepinephrine (NE) spillover rates in patients with essentialhypertension, particularly so in young hypertensive subjects, which inconcert with increased NE spillover from the heart, is consistent withthe hemodynamic profile typically seen in early hypertension andcharacterized by an increased heart rate, cardiac output andrenovascular resistance. It is now known that essential hypertension iscommonly neurogenic, often accompanied by pronounced sympathetic nervoussystem overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate and left ventricular ejection fraction. Thesefindings support the notion that treatment regimens that are designed toreduce renal sympathetic stimulation have the potential to improvesurvival in patients with heart failure.

Both chronic and end stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end stage renaldisease, plasma levels of norepinephrine above the median have beendemonstrated to be predictive for both all cause death and death fromcardiovascular disease. This is also true for patients suffering fromdiabetic or contrast nephropathy. There is compelling evidence thatsuggests that sensory afferent signals originating from the diseasedkidneys are major contributors to the initiation and sustainment ofelevated central sympathetic outflow in this patient group, whichfacilitates the occurrence of the well known adverse consequences ofchronic sympathetic overactivity such as hypertension, left ventricularhypertrophy, ventricular arrhythmias, sudden cardiac death, insulinresistance, diabetes and metabolic syndrome.

(i) Renal Sympathetic Efferent Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na+) reabsorption and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects and others.

(ii) Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the central nervoussystem via renal sensory afferent nerves. Several forms of “renalinjury” can induce activation of sensory afferent signals. For example,renal ischemia, reduction in stroke volume or renal blood flow, or anabundance of adenosine enzyme may trigger activation of afferent neuralcommunication. As shown in FIGS. 3A and 3B, this afferent communicationmight be from the kidney to the brain or might be from one kidney to theother kidney (via the central nervous system). These afferent signalsare centrally integrated and can result in increased sympatheticoutflow. This sympathetic drive is directed towards the kidneys, therebyactivating the RAAS and inducing increased renin secretion, sodiumretention, volume retention and vasoconstriction. Central sympatheticoveractivity also impacts other organs and bodily structures innervatedby sympathetic nerves such as the heart and the peripheral vasculature,resulting in the described adverse effects of sympathetic activation,several aspects of which also contribute to the rise in blood pressure.

The physiology therefore suggests that (i) denervation of tissue withefferent sympathetic nerves will reduce inappropriate renin release,salt retention, and reduction of renal blood flow, and that (ii)denervation of tissue with afferent sensory nerves will reduce thesystemic contribution to hypertension, and other disease statesassociated with increased central sympathetic tone, through its directeffect on the posterior hypothalamus as well as the contralateralkidney. In addition to the central hypotensive effects of afferent renaldenervation, a desirable reduction of central sympathetic outflow tovarious other sympathetically innervated organs such as the heart andthe vasculature is anticipated.

B. Additional Clinical Benefits of Renal Denervation

As provided above, renal denervation is likely to be valuable in thetreatment of several clinical conditions characterized by increasedoverall and particularly renal sympathetic activity such ashypertension, metabolic syndrome, insulin resistance, diabetes, leftventricular hypertrophy, chronic and end stage renal disease,inappropriate fluid retention in heart failure, cardio-renal syndromeand sudden death. Since the reduction of afferent neural signalscontributes to the systemic reduction of sympathetic tone/drive, renaldenervation might also be useful in treating other conditions associatedwith systemic sympathetic hyperactivity. Accordingly, renal denervationcan also benefit other organs and bodily structures innervated bysympathetic nerves, including those identified in FIG. 1. For example, areduction in central sympathetic drive may reduce the insulin resistancethat afflicts people with metabolic syndrome and Type II diabetics.Additionally, patients with osteoporosis are also sympatheticallyactivated and might also benefit from the downregulation of sympatheticdrive that accompanies renal denervation.

C. Achieving Intravascular Access to the Renal Artery

In accordance with the present invention, neuromodulation of a leftand/or right renal plexus (RP), which is intimately associated with aleft and/or right renal artery, may be achieved through intravascularaccess. As FIG. 4A shows, blood moved by contractions of the heart isconveyed from the left ventricle of the heart by the aorta. The aortadescends through the thorax and branches into the left and right renalarteries. Below the renal arteries, the aorta bifurcates at the left andright iliac arteries. The left and right iliac arteries descend,respectively, through the left and right legs and join the left andright femoral arteries.

As FIG. 4B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery can beexposed and cannulated at the base of the femoral triangle, justinferior to the midpoint of the inguinal ligament. A catheter can beinserted through this access site, percutaneously into the femoralartery and passed into the iliac artery and aorta, into either the leftor right renal artery. This comprises an intravascular path that offersminimally invasive access to a respective renal artery and/or otherrenal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. Catheterization ofeither the radial, brachial, or axillary artery may be utilized inselect cases. Catheters introduced via these access points may be passedthrough the subclavian artery on the left side (or via the subclavianand brachiocephalic arteries on the right side), through the aorticarch, down the descending aorta and into the renal arteries usingstandard angiographic technique.

D. Properties and Characteristics of the Renal Vasculature

Since neuromodulation of a left and/or right renal plexus (RP) may beachieved in accordance with the present invention through intravascularaccess, properties and characteristics of the renal vasculature mayimpose constraints upon and/or inform the design of apparatus, systemsand methods for achieving such renal neuromodulation. Some of theseproperties and characteristics may vary across the patient populationand/or within a specific patient across time, as well as in response todisease states, such as hypertension, chronic kidney disease, vasculardisease, end-stage renal disease, insulin resistance, diabetes,metabolic syndrome, etc. These properties and characteristics, asexplained below, may have bearing on the clinical safety and efficacy ofthe procedure and the specific design of the intravascular device.Properties of interest may include, for example, material/mechanical,spatial, fluid dynamic/hemodynamic and/or thermodynamic properties.

As discussed previously, a catheter can be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accesscan be challenging, for example, because, as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter and/ormay be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, further complicating minimallyinvasive access. Significant inter-patient variation may be seen, forexample, in relative tortuosity, diameter, length and/or atheroscleroticplaque burden, as well as in the take-off angle at which a renal arterybranches from the aorta. Apparatus, systems and methods for achievingrenal neuromodulation via intravascular access must account for theseand other aspects of renal arterial anatomy and its variation across thepatient population when minimally invasively accessing a renal artery.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renalartery. When the neuromodulatory apparatus comprises a thermal heatingelement, such as an electrode, consistent positioning and contact forceapplication between the thermal heating element and the vessel wall isimportant for predictability and safety. However, navigation is impededby the tight space within a renal artery, as well as tortuosity of theartery. Furthermore, respiration and/or the cardiac cycle may causesignificant movement of the renal artery relative to the aorta, and thecardiac cycle and/or the neuromodulatory apparatus may transientlydistend the renal artery, further complicating establishment of stablecontact.

Even after accessing a renal artery and facilitating stable contactbetween neuromodulatory apparatus and a luminal surface of the artery,nerves in and around the adventia of the artery must be safely modulatedvia the neuromodulatory apparatus. Safely applying thermal treatmentfrom within a renal artery is non-trivial given the potential clinicalcomplications associated with such treatment. For example, the intimaand media of the renal artery are highly vulnerable to thermal injury.As discussed in greater detail below, the Intima-Media Thicknessseparating the vessel lumen from its adventitia means that target renalnerves may be multiple millimeters distant from the luminal surface ofthe artery. Sufficient thermal energy must be delivered to the targetrenal nerves to modulate the target renal nerves without excessivelyheating and desiccating the vessel wall. Another potential clinicalcomplication associated with excessive heating is thrombus formationfrom coagulating blood flowing through the artery. Given that thisthrombus can cause a kidney infarct, thereby causing irreversible damageto the kidney, thermal treatment from within the renal artery must beapplied carefully. Accordingly, the complex fluid mechanic andthermodynamic conditions present in the renal artery during treatment,particularly those that may impact heat transfer dynamics at thetreatment site, can be important is applying thermal treatment fromwithin the renal artery.

The neuromodulatory apparatus should also be configured to allow foradjustable positioning and repositioning of the thermal element withinthe renal artery since location of treatment may also impact clinicalsafety and efficacy. For example, it may be tempting to apply a fullcircumferential treatment from within the renal artery given that therenal nerves may be spaced circumferentially around a renal artery.However, the full-circle lesion likely resulting from a continuouscircumferential treatment may create a heighten risk of renal arterystenosis, thereby negating any potential therapeutic benefit of therenal neuromodulation. Therefore, the formation of more complex lesionsalong a longitudinal dimension of the renal artery and/or repositioningof the neuromodulatory apparatus to multiple treatment locations may bedesirable. Additionally, variable positioning and repositioning of theneuromodulatory apparatus may prove to be useful in circumstances wherethe renal artery is particularly tortuous or where there are proximalbranch vessels off the renal artery main vessel, making treatment incertain locations challenging.

Based on the above described challenges of (1) renal arteryintervention, (2) consistent and stable placement of the thermal elementagainst the vessel wall, (3) safe application of thermal treatmentacross the vessel wall, and (4) positioning and repositioning thetreatment apparatus to allow for multiple treatment locations, variousindependent and dependent properties of the renal vasculature that maybe of interest include, for example, vessel diameter, length,intima-media thickness, coefficient of friction and tortuosity;distensibility, stiffness and modulus of elasticity of the vessel wall;peak systolic and end-diastolic blood flow velocity, as well as the meansystolic-diastolic peak blood flow velocity, mean/max volumetric bloodflow rate; specific heat capacity of blood and/or of the vessel wall,thermal conductivity of blood and/or of the vessel wall, thermalconvectivity of blood flow past a vessel wall treatment site and/orradiative heat transfer; and renal motion relative to the aorta, inducedby respiration and/or blood flow pulsatility, as well as the take-offangle of a renal artery relative to the aorta. These properties will bediscussed in greater detail with respect to the renal arteries. However,dependent on the apparatus, systems and methods utilized to achieverenal neuromodulation, such properties of the renal veins also may guideand/or constrain design characteristics.

Apparatus positioned within a renal artery must conform to the geometryof the artery. Renal artery vessel diameter, D_(RA), typically is in arange of about 2-10 mm, with an average of about 6 mm. Renal arteryvessel length, L_(RA), between its ostium at the aorta/renal arteryjuncture and its distal branchings, generally is in a range of about5-70 mm, more generally in a range of about 20-50 mm. Since the targetrenal plexus is embedded within the adventitia of the renal artery, thecomposite Intima-Media Thickness, IMT, (i.e., the radial outwarddistance from the artery's luminal surface to the adventitia containingtarget neural structures) also is notable and generally is in a range ofabout 0.5-2.5 mm, with an average of about 1.5 mm. Although a certaindepth of treatment is important to reach the target neural fibers, thetreatment should not be too deep (e.g., >5 mm from inner wall of therenal artery) to avoid non-target tissue and anatomical structures suchas the renal vein.

Apparatus navigated within a renal artery also must contend withfriction and tortuosity. The coefficient of friction, μ, (e.g., staticor kinetic friction) at the wall of a renal artery generally is quitelow, for example, generally is less than about 0.05, or less than about0.03. Tortuosity, τ, a measure of the relative twistiness of a curvedsegment, has been quantified in various ways. The arc-chord ratiodefines tortuosity as the length of a curve, L_(curve), divided by thechord, C_(curve), connecting the ends of the curve (i.e., the lineardistance separating the ends of the curve):

τ=Λ_(χυρωε) /X _(χυρωε)  (1)

Renal artery tortuosity, as defined by the arc-chord ratio, is generallyin the range of about 1-2.

The pressure change between diastole and systole changes the luminaldiameter of the renal artery, providing information on the bulk materialproperties of the vessel. The Distensibility Coefficient, DC, a propertydependent on actual blood pressure, captures the relationship betweenpulse pressure and diameter change:

ΔX=2*((Δ_(σψσ)−Δ_(δια))/Δ_(δια))/ΔΠ=2*(ΔΔ/Δ_(δια))/ΔΠ,  (2)

where D_(sys) is the systolic diameter of the renal artery, D_(dia) isthe diastolic diameter of the renal artery, and ΔD (which generally isless than about 1 mm, e.g., in the range of about 0.1 mm to 1 mm) is thedifference between the two diameters:

ΔΔ=Δ_(σψσ)−Δ_(δια),  (3)

The renal arterial Distensibility Coefficient is generally in the rangeof about 20-50 kPa⁻¹*10⁻³.

The luminal diameter change during the cardiac cycle also may be used todetermine renal arterial Stiffness, β. Unlike the DistensibilityCoefficient, Stiffness is a dimensionless property and is independent ofactual blood pressure in normotensive patients:

β=(λν[BΠ _(σψσ) /BΠ _(δια)])/(ΔΔ/Δ_(δια))  (4)

Renal arterial Stiffness generally is in the range of about 3.5-4.5.

In combination with other geometric properties of the renal artery, theDistensibility Coefficient may be utilized to determine the renalartery's Incremental Modulus of Elasticity, E_(inc):

E _(ινχ)=3(1+(ΛXΣA/IMXΣA))/ΔX,  (5)

where LCSA is the luminal cross-sectional area and IMCSA is theintima-media cross-sectional area:

ΛXΣA=π(Δ_(δια)/2)²  (6)

IMXΣA=π(Δ_(δια)/2+IMT)² −ΛXΣA  (7)

For the renal artery, LCSA is in the range of about 7-50 mm², IMCSA isin the range of about 5-80 mm², and E_(inc) is in the range of about0.1−0.4 kPa*10³.

For patients without significant Renal Arterial Stenosis (RAS), peakrenal artery systolic blood flow velocity, υ_(max-sys), generally isless than about 200 cm/s; while peak renal artery end-diastolic bloodflow velocity, υ_(max-dia), generally is less than about 150 cm/s, e.g.,about 120 cm/s.

In addition to the blood flow velocity profile of a renal artery,volumetric flow rate also is of interest. Assuming Poiseulle flow, thevolumetric flow rate through a tube, Φ, (often measured at the outlet ofthe tube) is defined as the average velocity of fluid flow through thetube, υ_(avg), times the cross-sectional area of the tube:

Φ=υ_(αωγ) *πP ²  (8)

By integrating the velocity profile (defined in Eq. 10 above) over all rfrom 0 to R, it can be shown that:

Φ=υ_(αωγ) *πP ²=(πP ⁴*ΔΠρ)/8ηΔξ  (9)

As discussed previously, for the purposes of the renal artery, η may bedefined as η_(blood), Δx may be defined as L_(RA), and R may be definedas D_(RA)/2. The change in pressure, ΔPr, across the renal artery may bemeasured at a common point in the cardiac cycle (e.g., via apressure-sensing guidewire) to determine the volumetric flow ratethrough the renal artery at the chosen common point in the cardiac cycle(e.g. during systole and/or during enddiastole). Volumetric flow rateadditionally or alternatively may be measured directly or may bedetermined from blood flow velocity measurements. The volumetric bloodflow rate through a renal artery generally is in the range of about500-1000 mL/min.

Thermodynamic properties of the renal artery also are of interest. Suchproperties include, for example, the specific heat capacity of bloodand/or of the vessel wall, thermal conductivity of blood and/or of thevessel wall, thermal convectivity of blood flow past a vessel walltreatment site. Thermal radiation also may be of interest, but it isexpected that the magnitude of conductive and/or convective heattransfer is significantly higher than the magnitude of radiative heattransfer.

The heat transfer coefficient may be empirically measured, or may becalculated as a function of the thermal conductivity, the vesseldiameter and the Nusselt Number. The Nusselt Number is a function of theReynolds Number and the Prandtl Number. Calculation of the ReynoldsNumber takes into account flow velocity and rate, as well as fluidviscosity and density, while calculation of the Prandtl Number takesinto account specific heat, as well as fluid viscosity and thermalconductivity. The heat transfer coefficient of blood flowing through therenal artery is generally in the range of about 500-6000 W/m²K.

An additional property of the renal artery that may be of interest isthe degree of renal motion relative to the aorta, induced by respirationand/or blood flow pulsatility. A patient's kidney, located at the distalend of the renal artery, can move as much as 5 cm cranially withrespiratory excursion. This may impart significant motion to the renalartery connecting the aorta and the kidney, thereby requiring from theneuromodulatory apparatus a unique balance of stiffness and flexibilityto maintain contact between the thermal treatment element and the vesselwall during cycles of respiration. Furthermore, the take-off anglebetween the renal artery and the aorta may vary significantly betweenpatients, and also may vary dynamically within a patient, e.g., due tokidney motion. The take-off angle generally may be in a range of about30°-135°.

These and other properties of the renal vasculature may imposeconstraints upon and/or inform the design of apparatus, systems andmethods for achieving renal neuromodulation via intravascular access.Specific design requirements may include accessing the renal artery,facilitating stable contact between neuromodulatory apparatus and aluminal surface or wall of the renal artery, and/or safely modulatingthe renal nerves with the neuromodulatory apparatus.

II. CATHETER APPARATUSES, SYSTEMS AND METHODS FOR RENAL NEUROMODULATION

A. Overview

FIG. 5 shows a system 10 for thermally inducing neuromodulation of aleft and/or right renal plexus (RP) through intravascular access.

As just described, the left and/or right renal plexus (RP) surrounds therespective left and/or right renal artery. The renal plexus (RP) extendsin intimate association with the respective renal artery into thesubstance of the kidney. The system thermally induces neuromodulation ofa renal plexus (RP) by intravascular access into the respective left orright renal artery.

The system 10 includes an intravascular treatment device 12. Thetreatment device 12 provides access to the renal plexus (RP) through anintravascular path 14 that leads to a respective renal artery, as FIG.6A shows.

As FIG. 5 shows, the treatment device 12 includes an elongated shaft 16having a proximal end region 18 and a distal end region 20.

The proximal end region 18 of the elongated shaft 16 is connected to ahandle assembly 200. The handle assembly 200 is sized and configured tobe securely or ergonomically held and manipulated by a caregiver (see,e.g., FIG. 19A) outside an intravascular path 14 (see, e.g., FIG. 6A).By manipulating the handle assembly 200 from outside the intravascularpath 14, the caregiver can advance the elongated shaft 16 through thetortuous intravascular path 14 and remotely manipulate or actuate thedistal end region 20. Image guidance, e.g., CT, radiographic, IVUS, OCTor another suitable guidance modality, or combinations thereof, can beused to aid the caregiver's manipulation.

As shown in FIG. 6B, the distal end region 20 of the elongated shaft 16can flex in a substantial fashion to gain entrance into a respectiveleft/right renal artery by manipulation of the elongated shaft 16. Asshown in FIGS. 24A and 24B, the distal end region 20 of the elongatedshaft 16 can gain entrance to the renal artery via passage within aguide catheter 94. The distal end region 20 of the elongated shaft 16carries at least one thermal element 24 (e.g., thermal heating element,energy delivery element, radiofrequency electrode, electrode, cooledradiofrequency electrode, electrically resistive heating element,cryoablation applicator, microwave antenna, ultrasound transducer, highintensity focused ultrasound transducer, laser emitter). The thermalheating element 24 is also specially sized and configured formanipulation and use within a renal artery.

As FIG. 6B shows (and as will be described in greater detail later),once entrance to a renal artery is gained, further manipulation of thedistal end region 20 and the thermal heating element(s) 24 within therespective renal artery establishes proximity to and alignment betweenthe thermal heating element(s) 24 and tissue along an interior wall ofthe respective renal artery. In some embodiments, manipulation of thedistal end region 20 will also facilitate contact between the thermalheating element(s) 24 and wall of the renal artery. In the context ofthe present application, the phrasing “contact between an energydelivery element and a wall of the renal artery” generally meanscontiguous physical contact with or without atraumatic distension of therenal artery wall and without puncturing or perforating the renal arterywall.

As will be described in greater detail later, in the representativeembodiment of FIG. 6B, the thermal heating element 24 of distal endregion 20 is positioned along a distal tip or end of the distal endregion, e.g., at a distal end of an optional third or distal flexurezone 44. However, it should be understood that the distal end region 20optionally may comprise one or more additional thermal heating elementsthat are positioned relatively more proximal. When multiple thermalheating elements are provided, the thermal heating elements may deliverpower independently (i.e., may be used in a monopolar fashion), eithersimultaneously or progressively, and/or may deliver power between anydesired combination of the elements (i.e., may be used in a bipolarfashion). Furthermore, the caregiver optionally may be capable ofdynamically choosing which thermal heating element(s) are used for powerdelivery in order to form highly customizable lesion(s) within the renalartery, as desired.

In one representative embodiment shown in FIG. 7A, one or moreadditional thermal heating elements 24 a optionally may be positionedproximally of thermal heating element 24, e.g., along a third flexurezone 44, at a proximal region of the optional third flexure zone 44and/or at a distal region of an optional second or intermediate flexurezone 34 for contacting an internal wall of the renal artery atposition(s) longitudinally spaced, but generally in angular alignment,with the distally located thermal heating element 24. The spacing of thethermal heating elements 24 and 24 a may be specified to provide adesired spacing between lesions formed when using the elements within arenal artery. In one representative embodiment, thermal heating elements24 and 24 a are spaced apart as far as about 1 cm. In other embodiments,the spacing between thermal heating elements 24 and 24 a is in the rangeof about 2 mm to about 5 mm. In one representative embodiment, thethermal heating elements 24 and 24 a are spaced apart about 5 mm. Inanother representative embodiment, the thermal heating elements 24 and24 a are spaced apart about 2 mm.

Additionally or alternatively, as shown in FIG. 7B, one or more thermalheating elements 24 b may be positioned relatively more proximal forcontacting an internal wall of the renal artery at position(s) that arelongitudinally and angularly spaced (e.g., in angular opposition) fromthe distally located thermal heating element 24. Such thermal heatingelement(s) 24 b may, for example, be positioned at an apex of a bendformed during deflection of the optional second flexure zone 34, at aproximal region of the optional second flexure zone 34, and/or at adistal region of a first or proximal flexure zone 32. The spacingseparating thermal heating element 24 b from thermal heating element 24and/or from optional thermal heating element 24 a may be specified asdesired to provide desired longitudinal and angular spacing betweenlesions formed within renal vasculature. In one representativeembodiment, thermal heating elements 24 and 24 b are spaced apart about5 mm to about 25 mm. In another representative embodiment, the thermalheating elements 24 and 24 b can be spaced as far as about 30 mm. Inanother representative embodiment, the thermal heating elements 24 and24 b are spaced apart about 11 mm. In still another representativeembodiment, the thermal heating elements 24 and 24 b are spaced apartabout 17.5 mm.

As also will be described in greater detail later, different sections ofthe elongated shaft 16 serve different mechanical functions when in use.The sections are thereby desirably differentiated in terms of theirsize, configuration and mechanical properties for (i) percutaneousintroduction into a femoral artery through a small-diameter access site;(ii) atraumatic passage through the tortuous intravascular path 14through an iliac artery, into the aorta, and into a respectiveleft/right renal artery, including (iii) significant flexure near thejunction of the left/right renal arteries and aorta to gain entry intothe respective left or right renal artery; (iv) controlled translation,deflection, rotation and/or actuation within the respective renal arteryto attain proximity to and a desired alignment with an interior wall ofthe respective renal artery; (v) the placement of at least one thermalheating element 24 into contact with tissue on the interior wall; andvi) allowing substantially stable contact force between the at least onethermal heating element and the interior wall during motion of the renalartery with respect to the aorta due to respiration and/or blood flowpulsatility; and (vii) repositioning via retraction and/or deflection ina second direction and/or rotation within the renal artery forsubsequent treatment(s).

Referring back to FIG. 5, the system 10 also includes a generator 26(e.g., a thermal energy generator). Under the control of the caregiveror automated control algorithm 102 (as will be described in greaterdetail later), the generator 26 generates a selected form and magnitudeof energy. A cable 28 operatively attached to the handle assembly 200electrically connects the thermal heating element 24 to the generator26. At least one supply wire (not shown) passing along the elongatedshaft 16 or through a lumen in the elongated shaft 16 from the handleassembly 200 to the thermal heating element 24 conveys the treatmentenergy to the thermal heating element 24. A control mechanism, such asfoot pedal 100, can be connected (e.g., pneumatically connected orelectrically connected) to the generator 26 to allow the operator toinitiate, terminate and, optionally, adjust various operationalcharacteristics of the generator, including, but not limited to, powerdelivery.

For systems that provide for the delivery of a monopolar electric fieldvia the thermal heating element 24, a neutral or dispersive electrode 38can be electrically connected to the generator 26 and attached to theexterior of the patient. Additionally, one or more sensors 52 (see,e.g., FIGS. 10 and 24), such as one or more temperature (e.g.,thermocouple, thermistor, etc.), impedance, pressure, optical, flow,chemical or other sensors, can be located proximate to or within thethermal heating element and connected to one or more of the supplywires. For example, a total of two supply wires can be included, inwhich both wires could transmit the signal from the sensor and one wirecould serve dual purpose and also convey the energy to the thermalheating element. Alternatively, both wires could transmit energy to thethermal heating element.

Once proximity between, alignment with, and contact between the thermalheating element 24 and tissue are established within the respectiverenal artery (as FIG. 6B shows), the purposeful application of energyfrom the generator 26 to tissue by the thermal heating element 24induces one or more desired neuromodulating effects on localized regionsof the renal artery and adjacent regions of the renal plexus (RP), whichlay intimately within or adjacent to the adventitia of the renal artery.The purposeful application of the neuromodulating effects can achieveneuromodulation along all or a portion of the RP.

The neuromodulating effects can include thermal ablation, non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating), and electromagnetic neuromodulation. Desired thermalheating effects may include raising the temperature of target neuralfibers above a desired threshold to achieve non-ablative thermalalteration, or above a higher temperature to achieve ablative thermalalteration. For example, the target temperature can be above bodytemperature (e.g., approximately 37° C.) but less than about 45° C. fornon-ablative thermal alteration, or the target temperature can be about45° C. or higher for the ablative thermal alteration. Desiredelectromagnetic neuromodulation effects may include altering theelectrical signals transmitted in a nerve.

Further details of special size, configuration, and mechanicalproperties of the elongated shaft 16, the distal end region 20 and thethermal heating element 24, as well as other aspects of the system 10,will now be described. In still other embodiments, the system 10 mayhave a different configuration and/or include different features. Forexample, alternative multi-thermal heating element devices, such asmulti-electrode baskets, spirals or lassos, or balloon expandabledevices, may be implemented to intravascularly deliver neuromodulatorytreatment with or without contacting the vessel wall.

B. Size and Configuration of the Elongated Shaft for AchievingIntravascular Access to a Renal Artery

As explained above, intravascular access to an interior of a renalartery can be achieved, for example, through the femoral artery. As FIG.6B shows, the elongated shaft 16 is specially sized and configured toaccommodate passage through this intravascular path 14, which leads froma percutaneous access site in the femoral artery to a targeted treatmentsite within a renal artery. In this way, the caregiver is able to orientthe thermal heating element 24 within the renal artery for its intendedpurpose.

For practical purposes, the maximum outer dimension (e.g., diameter) ofany section of the elongated shaft 16, including the thermal heatingelement 24 it carries, is dictated by the inner diameter of the guidecatheter through which the elongated shaft 16 is passed. Assuming, forexample, that an 8 French guide catheter (which has an inner diameter ofapproximately 0.091 inches) would likely be, from a clinicalperspective, the largest guide catheter used to access the renal artery,and allowing for a reasonable clearance tolerance between the thermalheating element 24 and the guide catheter, the maximum outer dimensioncan be realistically expressed as being less than or equal toapproximately 0.085 inches. However, use of a smaller 5 French guidecatheter 94 may require the use of smaller outer diameters along theelongated shaft 16. For example, a thermal heating element 24 that is tobe routed within a 5 French guide catheter would have an outer dimensionof no greater than 0.053 inches. In another example, a thermal heatingelement 24 that is to be routed within a 6 French guide catheter wouldhave an outer dimension of no great than 0.070 inches.

1. Force Transmitting Section

As FIG. 8A shows, the proximal end region 18 of the elongated shaft 16includes, coupled to the handle assembly 200, a force transmittingsection 30. The force transmitting section 30 is sized and configured topossess selected mechanical properties that accommodate physical passagethrough and the transmission of forces within the intravascular path 14,as it leads from the accessed femoral artery (left or right), throughthe respective iliac branch artery and into the aorta, and in proximityto the targeted renal artery (left or right). The mechanical propertiesof the force transmitting section 30 include at least a preferredeffective length (expressed in inches or centimeters). It should beunderstood that the term force transmitting section can be usedinterchangeably with elongated tubular shaft or proximal forcetransmitting section.

As FIG. 8A shows, the force transmitting section 30 includes a preferredeffective length L1. The preferred effective length L1 is a function ofthe anatomic distance within the intravascular path 14 between theaccess site and a location proximate to the junction of the aorta andrenal arteries. The preferred effective length L1 can be derived fromtextbooks of human anatomy, augmented by a caregiver's knowledge of thetargeted site generally or as derived from prior analysis of theparticular morphology of the targeted site. The preferred effectivelength L1 is also dependent on the length of the guide catheter that isused, if any. In a representative embodiment, for a normal human, thepreferred effective length L1 comprises about 30 cm to about 110 cm. Ifno guide catheter is used, then the preferred effective length L1comprises about 30 cm to about 35 cm. If a 55 cm length guide catheteris used, then the preferred effective length L1 comprises about 65 cm toabout 70 cm. If a 90 cm length guide catheter is used, then thepreferred effective length L1 comprises about 95 cm to about 105 cm.

The force transmitting section 30 also includes a preferred axialstiffness and a preferred torsional stiffness. The preferred axialstiffness expresses the capability of the force transmitting section 30to be advanced or withdrawn along the length of the intravascular path14 without buckling or substantial deformation. Since some axialdeformation is necessary for the force transmitting section 30 tonavigate the tortuous intravascular path 14 without providing too muchresistance, the preferred axial stiffness of the force transmittingsection should also provide this capability. The preferred torsionalstiffness expresses the capability of the force transmitting section 30to rotate the elongated shaft 16 about its longitudinal axis along itslength without kinking or permanent deformation. As will be described ingreater detail later, the ability to advance and retract, as well asrotate, the distal end region 20 of the elongated shaft 16 within therespective renal artery is desirable.

The desired magnitude of axial stiffness and rotational stiffness forthe force transmitting section 30 can be obtained by selection ofconstituent material or materials to provide a desired elastic modulus(expressed in terms, e.g., of a Young's Modulus (E)) indicative of axialand torsional stiffnesses, as well as selecting the construct andconfiguration of the force transmitted section in terms of, e.g., itsinterior diameter, outer diameter, wall thickness, and structuralfeatures, including cross-sectional dimensions and geometry.Representative examples are described in greater detail below.

2. First Flexure Zone

As FIGS. 8A and 8B show, the distal end region 20 of the elongated shaft16 is coupled to the force transmitting section 30. The length L1 of theforce transmitting section 30 generally serves to bring the distal endregion 20 into the vicinity of the junction of the respective renalartery and aorta (as FIG. 6B shows). The axial stiffness and torsionalstiffness of the force transmitting region transfer axial and rotationforces from the handle assembly 200 to the distal end region 20, as willbe described in greater detail later. It should be understood that theterm first flexure zone can be used interchangeably with flexibletubular structure.

As shown in FIG. 8B, the distal end region 20 includes a first orproximal flexure zone 32 proximate to the force transmitting section 30.The first flexure zone 32 is sized and configured to have mechanicalproperties that accommodate significant flexure or bending at aprescribed preferred access angle α1 and provide for the transmission oftorque during rotation, without fracture, collapse, or significanttwisting of the elongated shaft 16. The proximal flexure zone 32 shouldaccommodate flexure sufficient for the distal end region 20 to advancevia a guide catheter into the renal artery without substantiallystraightening out the guide catheter.

Angle α1 is defined by the angular deviation that the treatment device12 must navigate to transition between the aorta (along which the forcetransmitting section 30 is aligned) and the targeted renal artery (alongwhich the distal end region 20 is aligned) (this is also shown in FIG.6B). This is the angle that the first flexure zone 32 must approximateto align the distal end region 20 of the elongated shaft 16 with thetargeted renal artery, while the force transmitting section 30 of theelongated shaft 16 remains aligned with the native axis of the aorta (asFIG. 6B shows). The more tortuous a vessel, or the more severe thetake-off angle between the renal artery and the aorta, the greater bendthe first flexure zone 32 will need to make for the distal end region ofthe treatment device to access the renal artery and the smaller theangle α1.

When the catheter is outside the patient and the first flexure zone 32is in a substantially straight, non-deflected configuration, angle α1(as shown in FIG. 8B) is approximately 180°. Upon full deflection of thefirst flexure zone 32, the angle α1 is reduced to anywhere between about30° and 180°. In a representative embodiment, upon full deflection angleα1 is about 30° to about 135°. In another representative embodiment,upon full deflection angle α1 is about 90°.

The first flexure zone 32 is sized and configured to possess mechanicalproperties that accommodate significant, abrupt flexure or bending atthe access angle α1 near the junction of the aorta and the renal artery.Due to its size, configuration, and mechanical properties, the proximalflexure zone 32 must resolve these flexure or bending forces withoutfracture, collapse, distortion, or significant twisting. Such flexure orbending of the first flexure zone may occur at least in part within thedistal region of a guide catheter without substantially straighteningout the guide catheter. The resolution of these flexure or bendingforces by the first flexure zone 32 makes it possible for the distal endregion 20 of the elongated shaft 16 to gain entry along theintravascular path 14 into a targeted left or right renal artery.

The first flexure zone 32 is sized and configured in length L2 to beless than length L1 (see FIG. 8A). That is because the distance betweenthe femoral access site and the junction of the aorta and renal artery(typically approximating about 40 cm to about 55 cm) is generallygreater than the length of a renal artery between the aorta and the mostdistal treatment site along the length of the renal artery, which istypically less than about 7 cm. The preferred effective length L2 can bederived from textbooks of human anatomy, augmented with a caregiver'sknowledge of the site generally or as derived from prior analysis of theparticular morphology of the targeted site. For example, the length L2generally may be less than about 15 cm, e.g., may be less than about 10cm. In one representative embodiment, the length L2 may be about 9 cm.

Desirably, the length L2 is selected to make it possible to rest aportion of the first flexure zone 32 partially in the aorta at or nearthe length L1, as well as rest the remaining portion of the firstflexure zone 32 partially within the renal artery (as FIG. 6B shows). Inthis way, the first flexure zone 32 defines a transitional bend that issupported and stable within the vasculature.

In the deflected configuration of FIG. 8B, the first flexure zone 32comprises a radius of curvature RoC₁. In embodiments where the curvatureof first flexure zone 32-does not vary or is consistent along the lengthL2, the length L2 and the deflection angle α1 may define the radius ofcurvature RoC₁. It should be understood that the curvature of firstflexure zone 32, and thereby the radius of curvature RoC₁ of the firstflexure zone, alternatively may vary along the length L2.

In such embodiments where the curvature does not vary, the length L2 maydefine a fraction (180°−α1)/360° of the circumference C₁ of a circlewith an equivalent radius of curvature RoC₁. Thus, the circumference ofsuch an equivalent circle is:

$\begin{matrix}\begin{matrix}{C_{1} = {\frac{360{^\circ}}{\left( {{180{^\circ}} - {\alpha 1}} \right)} \times L\; 2}} \\{= {2\pi \times {RoC}_{1}}}\end{matrix} & (10)\end{matrix}$

Solving for the radius of curvature RoC₁:

$\begin{matrix}{{RoC}_{1} = \frac{360{^\circ} \times L\; 2}{2\pi \times \left( {{180{^\circ}} - {\alpha 1}} \right)}} & (11)\end{matrix}$

Thus, in a representative embodiment of the first flexure zone 32 wherethe curvature of the first flexure zone does not vary along the lengthL2, where the length L2 is less than or equal to about 9 cm, and wherethe angle α1 is about 30° to about 135°, the radius of curvature RoC₁ isabout 3.5 cm to about 11.5 cm. In a representative embodiment of firstflexure zone 32 where the curvature of the first flexure zone does notvary along the length L2, where the length L2 is less than or equal toabout 9 cm, and where the angle α1 is less than or equal to about 90°,the radius of curvature RoC₁ is less than or equal to about 5.75 cm.

As will be apparent, Equation (11) may be rearranged such that thelength L2 and the radius of curvature RoC₁ define the angle α1.Furthermore, Equation (11) may be rearranged such that the radius ofcurvature RoC₁ and the angle α1 define the length L2. Thus, inembodiments where the curvature of first flexure zone 34 does not varyalong the length L2, any one of the length L2, angle α1 and radius ofcurvature RoC₁ may be specified by specifying the other two variables.

As will be described in greater detail later, and as shown in FIG. 6B,the length L2 of the first flexure zone 32 optionally does not extendthe full length of the targeted length of the renal artery. That isbecause the distal end region 20 of the elongated shaft 16 optionallyincludes one or more additional flexure zones, distal to the firstflexure zone 32 (toward the substance of the kidney), to accommodateother different functions important to the therapeutic objectives of thetreatment device 12. As will be described later, the ability to transmittorque through the first flexure zone 32 makes it possible to rotate thethermal heating device to properly position the thermal heating elementwithin the renal artery for treatment.

In terms of axial and torsional stiffness, the mechanical properties offirst flexure zone 32 can, and desirably do, differ from the mechanicalproperties of the force transmitting section 30. This is because theproximal flexure zone 32 and the force transmitting section servedifferent functions while in use. Alternatively, the mechanicalproperties of proximal flexure zone 32 and force transmitting section 30can be similar.

The force transmitting section 30 serves in use to transmit axial loadand torque over a relatively long length (L1) within the vascularpathway. In contrast, the first flexure zone 32 needs to transmit axialload and torque over a lesser length L2 proximate to or within arespective renal artery. Importantly, the first flexure zone 32 mustabruptly conform to an access angle α1 near the junction of the aortaand the respective renal artery, without fracture, collapse, significanttwisting, or straightening a guide catheter imparting the access angleα1. This is a function that the force transmitting zone need notperform. Accordingly, the first flexure zone 32 is sized and configuredto be less stiff and to possess greater flexibility than the forcetransmitting section 30.

Additionally, the first flexure zone 32 may allow thermal heatingelement(s) 24 to maintain stable contact with the interior wall of therenal artery as the respective kidney moves due to patient respiration.As a patient breathes the kidney may move, causing the renal artery topivot about the ostium, where the renal artery joins the aorta. Stablecontact between the thermal heating element(s) 24 and the inner wall ofthe renal artery is desired during energy delivery. Therefore, thethermal heating element(s) 24 must move, along with the renal artery,relative to the aorta. The mechanical properties of the first flexurezone 32 that accommodate significant, abrupt flexure or bending at theaccess angle α1 near the junction of the aorta and the renal artery alsoallow the sections of the catheter distal to the first flexure zone 32to pivot about the ostium without significant impediment, allowing thethermal heating element to maintain stable contact force with the innerwall of the renal artery. In some embodiments, second flexure zone 34distal to first flexure zone 32 may become more stiff than the firstflexure zone 32 when it is controllably deflected. The additionalstiffness of second flexure zone 34 helps maintain a stable contactforce between the energy delivery element 24 and an inner wall of therenal artery and allows the catheter to move with the renal arteryrelative to the aorta with sufficient freedom due to the flexibledeformation of the first flexure zone 32. The renal artery pivots aboutthe juncture with the aorta such that movement of the renal arteryincreases with distance from the juncture with the aorta. The length ofthe distal end region 20 distal to the first flexure zone 32 along withthe length of the first flexure zone 32 is configured such that anincreasing portion of the first flexure zone 32 is positioned in therenal artery the more distal the treatment site to provide sufficientincreased flexibility in the region of the juncture with the aorta toallow stable contact force between the energy delivery element 24 andthe more distal treatment site of the inner wall of the renal artery,especially during increased motion at the more distal treatment site.

The desired magnitude of axial stiffness, rotational stiffness, andflexibility for the proximal flexure zone 32 can be obtained byselection of constituent material or materials to provide a desiredelastic modulus (expressed, e.g., in terms of a Young's Modulus (E))indicative of flexibility, as well as selecting the construct andconfiguration of the force transmitting section, e.g., in terms of itsinterior diameter, outer diameter, wall thickness, and structuralfeatures, including cross-sectional dimensions and geometry.Representative examples will be described in greater detail later.

Although it is desirable that the force transmitting section 30 and thefirst flexure zone 32 have stiffness and flexibility properties that areunique to their respective functions, it is possible that the forcetransmitting section 30 and the first flexure zone 32 comprise the samematerials, size and geometric configuration such that the forcetransmitting section 30 and the first flexure zone 32 constitute thesame section.

3. Second Flexure Zone

As shown in FIGS. 8A, 8B, and 8C, the distal end region 20 of theelongated shaft 16 also includes, distal to the first or proximalflexure zone 32, a second or intermediate flexure zone 34. It should beunderstood that the term second flexure zone can be used interchangeablywith deflectable section or intermediate flexure zone or deflectabletubular body or multi-directional deflectable assembly.

The second flexure zone 34 is sized, configured, and has the mechanicalproperties that accommodate additional flexure or bending, independentof the first flexure zone 32, at a preferred contact angle α2, withoutfracture, collapse, or significant twisting. The second flexure zone 34should also accommodate flexure sufficient for the distal end region 20to advance via a guide catheter into the renal artery withoutstraightening out the guide catheter. The second flexure zone 34 isfurther configured for controllable deflection in multiple directions.

Controlled, multi-directional bending of the second flexure zone mayfacilitate placement of thermal heating element 24 into stable contactwith a treatment site or with multiple treatment sites within a renalartery. Such control over placement of the thermal heating element maybe especially useful in patients with relatively tortuous vessels. Forexample, if placement of the thermal heating element 24 into contactwith a renal arterial treatment site is sub-optimal under controlledbending of the second flexure zone in a first direction, the secondflexure zone may be controllably deflected in a second direction to moreoptimally place the thermal heating element into contact with thetreatment site, or with an alternative or additional treatment site.Deflection in a first direction can achieve placement of a thermalelement 24 in contact with a first location in a renal artery, forexample as shown in FIG. 6B. Deflection in a second direction canachieve placement of the thermal element 24 in contact with a secondlocation in the renal artery, for example as shown in FIG. 6C.Additionally, multi-direction controllable deflection can facilitateprecise placement of a thermal element 24 by reducing the need fortwisting the catheter when manipulating the distal end region 20.

Furthermore, stable contact and energy delivery may be achievable atmultiple treatment sites via controlled multi-directional deflection ofthe second flexure zone. For example, as shown in FIG. 24B a thermalelement 24 may be placed in contact with an inner wall of a renal arterywithout controlled deflection of the second flexure zone 24. However,contact may not be stable and during energy delivery, especially whilethe artery undergoes motion due to respiration and blood pulsatility,the thermal element 24 could intermittently lose contact or contactcould migrate resulting in a less effective treatment. By deflecting thesecond flexure zone 34, the thermal element can be radially deflectedfrom the axis of the elongated body 16; in addition to the contactbetween the thermal element and the artery wall, contact can be madebetween a second location on the distal end region 20 for example on thesecond flexure zone (as shown in FIG. 25A); and the stiffness of thesecond flexure zone can be increased to hold the thermal element instable contact with the artery wall while the flexibility of a portionof the first flexure zone allows the distal end region 20 to pivot aboutthe junction of the renal artery and aorta. These functions contributeto increased stable contact force between the thermal element 24 and thetreatment site.

The preferred contact angle α2 is defined by the angle through which thethermal heating element 24 can be radially deflected within the renalartery to establish contact between the thermal heating element 24 andan inner wall of the respective renal artery (as FIG. 6B shows). Themagnitude of the contact angle α2 and the length of the second flexurezone L3 preferably are based on the native inside diameter of therespective renal artery where the thermal heating element 24 rests,which may vary between about 2 mm and about 10 mm, as well as thediameter of the thermal heating element 24. It is most common for thediameter of the renal artery to vary between about 2 mm and about 8 mm,with a mean diameter of about 6 mm. The contact angle α2 when deflectedin a first direction can be equal to a contact angle α2 when deflectedin a second direction. Alternatively, a contact angle when deflected ina second direction can be different from a contact angle when deflectedin a first direction.

The second flexure zone 34 extends distally from the first flexure zone32 for a length L3 into the targeted renal artery (see FIG. 6B).Desirably, the length L3 is selected, taking into account the length L2of the proximal flexure zone 32 that extends into the renal artery, aswell as the anatomy of the respective renal artery, to actively placethe thermal heating element 24 (carried at the end of the distal endregion 20) at or near the targeted treatment site (as FIG. 6B shows).The length L3 can be derived, taking the length L2 into account, fromtextbooks of human anatomy, together with a caregiver's knowledge of thesite generally or as derived from prior analysis of the particularmorphology of the targeted site.

As FIG. 8A shows, the second flexure zone 34 is desirably sized andconfigured in length L3 to be less than length L2. This is because, interms of length, the distance required for actively deflecting thethermal heating element 24 into contact with a wall of the renal arteryis significantly less than the distance required for bending theelongated shaft 16 to gain access from the aorta into the renal artery.Thus, the length of the renal artery is occupied in large part by thesecond flexure zone 34 and not as much by the first flexure zone 32.

In a representative embodiment, L2 is less than or equal to about 9 cmand L3 is about 5 mm to about 15 mm. In certain embodiments,particularly for treatments in relatively long blood vessels, L3 can beless than or equal to about 20 mm. In another representative embodiment,and as described later in greater detail, L3 is less than or equal toabout 12.5 mm. In another representative embodiment, particularlywherein second flexure zone comprises a hinge joint, L3 is no greaterthan 3 mm.

When the catheter is outside the patient and the second flexure zone 34is in a substantially straight, non-deflected configuration, contactangle α2 (as shown in FIG. 8C) is approximately 180°. Upon fulldeflection of the second flexure zone 34, the angle α2 is reduced toanywhere between about 45° and 180°. In a representative embodiment,upon full deflection, angle α2 is about 75° to about 135°. In anotherrepresentative embodiment, upon full deflection, angle α2 is less thanor equal to about 90°.

In the deflected configuration of FIG. 8C, the second flexure zone 34comprises a radius of curvature RoC₂. In embodiments where the curvatureof second flexure zone 34 does not vary or is consistent along thelength L3, the length L3 and the contact angle α2 may define the radiusof curvature RoC₂. It should be understood that the curvature of secondflexure zone 34, and thereby the radius of curvature RoC₂ of the secondflexure zone, alternatively may vary along the length L3.

In such embodiments where the curvature does not vary, the length L3 maydefine a fraction (180°−α2)/360° of the circumference C₂ of a circlewith an equivalent radius of curvature RoC₂. Thus, the circumference ofsuch an equivalent circle is:

$\begin{matrix}\begin{matrix}{C_{2} = {\frac{360{^\circ}}{\left( {{180{^\circ}} - {\alpha 2}} \right)} \times L\; 3}} \\{= {2\pi \times {RoC}_{2}}}\end{matrix} & (12)\end{matrix}$

Solving for the radius of curvature RoC₂:

$\begin{matrix}{{RoC}_{2} = \frac{360{^\circ} \times L\; 3}{2\pi \times \left( {{180{^\circ}} - {\alpha 2}} \right)}} & (13)\end{matrix}$

Thus, in a representative embodiment of the second flexure zone 34 wherethe curvature of the second flexure zone does not vary along the lengthL3, where the length L3 is about 5 mm to about 20 mm, and where thecontact angle α2 is about 75° to about 135°, the radius of curvatureRoC₂ is about 3 mm to about 25 mm. In a representative embodiment ofintermediate flexure zone 34 where the curvature of the intermediateflexure zone does not vary along the length L3, where the length L3 isless than or equal to about 12.5 mm, and where the angle α2 is about 75°to about 135°, the radius of curvature RoC₂ is about 7 mm to about 16mm. In a representative embodiment of second flexure zone 34 where thecurvature of the second flexure zone does not vary along the length L3,where the length L3 is less than or equal to about 12.5 mm, and wherethe angle α2 is less than or equal to about 90°, the radius of curvatureRoC₂ is less than or equal to about 8 mm. In a representative embodimentwhere the second flexure zone 34 comprises a joint the angle α2 isobtained about a pivot axis in the joint and therefore a radius ofcurvature does not exist.

As will be apparent, Equation (13) may be rearranged such that thelength L3 and the radius of curvature RoC₂ define the contact angle α2.Furthermore, Equation (13) may be rearranged such that the radius ofcurvature RoC₂ and the angle α2 define the length L3. Thus, inembodiments where the curvature of second flexure zone 34 does not varyalong the length L3, any one of the length L3, angle α2 and radius ofcurvature RoC₂ may be specified by specifying the other two variables.

In the deflected configuration of FIG. 8C, the second flexure zone 34locates the thermal heating element 24 at a dimension Y from alongitudinal axis A of the second flexure zone 34 just distal of thefirst flexure zone 32. The dimension Y can vary from about 2 mm to about20 mm. In some configurations, and given the dimension of most renalarteries, the dimension Y can be from about 5 mm to about 15 mm. Sincethe average diameter of most renal arteries is generally less than 10 mmas described below, it may be desirable for dimension Y to be less thanor equal to 10 mm. For example the Y dimension can be 6 mm or 8 mm oranywhere between and including 6 to 10 mm.

By way of example, the average diameter of a human renal artery is fromabout 2 mm to about 8 mm, but may range from about 2 mm to about 10 mm.Accordingly, if the distal end of the first flexure zone 32 werepositioned adjacent to a wall of an artery having an 8 mm diameter, thesecond flexure zone 34 would be capable of deflection sufficient for thethermal heating element 24 to contact the opposite wall of the artery.In other embodiments, however, the dimension Y may have a differentvalue and may be oversized to facilitate contact in a straight or curvedvessel. The second flexure zone 34 is also configured to locate thethermal heating element 24 at a dimension X from a distal end of thefirst flexure zone 32. The dimension X can vary, e.g., based on thedimension Y and the length L3.

As FIG. 8C shows, having first and second flexure zones 32 and 34, thedistal end region 20 of the elongated shaft 16 can, in use, be placedinto a complex, multi-bend structure 36. The complex, multi-bendstructure 36 comprises one deflection region at the access angle α1 overa length L2 (the first flexure zone 32) and a second deflection regionat the contact angle α2 over a length L3 (the second flexure zone 34).In the complex, multi-bend, both L2 and L3 and angle α1 and angle α2 candiffer. This is because the angle α1 and length L2 are specially sizedand configured to gain access from an aorta into a respective renalartery through a femoral artery access point, and the angle α2 andlength L3 are specially sized and configured to align a thermal heatingelement 24 with an interior wall inside the renal artery.

In the illustrated embodiment (see, e.g., FIG. 8C), the second flexurezone 34 is sized and configured to allow a caregiver to remotely deflectthe second flexure zone 34 within the renal artery in multipledirections, to radially position the thermal heating element 24 intocontact with an inner wall of the renal artery.

In the illustrated embodiment, a control mechanism is coupled to thesecond flexure zone 34. The control mechanism includes one or moreflexure control elements (for example control wire(s) 40) attached tothe distal end of the second flexure zone 34 (a representativeembodiment is shown in FIGS. 23B and 23C and will be described ingreater detail later). Each flexure control element 40 is passedproximally through the elongated shaft 16 and coupled to an actuator 260(also called a flexure controller) on the handle assembly 200. Operationof the actuator 260 (e.g., by the caregiver pulling proximally on orpushing forward the actuator 260) pulls the control wire 40 back toapply a tension to the control wire which applies compression to theintermediate flexure zone 34 (as FIGS. 8C and 14C show). The compressiveforce in combination with the directionally biased compression(described further below) of the second flexure zone 34 deflects thesecond flexure zone 34 and, thereby, radially moves the thermal heatingelement 24 toward an interior wall of the renal artery (as FIG. 6Bshows).

Desirably, as will be described in greater detail later, the distal endregion 20 of the elongated shaft 16 can be sized and configured to varythe compressibility of the second flexure zone 34 about itscircumference. The variable circumferential compressibility impartspreferential and directional bending to the intermediate flexure zone 34(i.e., directionally biased compressibility). In response to operationof the actuator 260, the second flexure zone 34 may be configured tobend in a single preferential direction. Deflection in additionaldirections can be achieved in response to operation of an actuator 260in a different direction applying tension to other control wires.Representative embodiments depicting multidirectional bending withmultiple control wires will be described later in greater detail.

Multiple direction deflection of second flexure zone 34 alternativelycan be achieved with one control wire, as will be discussed in moredetail later. As shown in FIGS. 22A to 22F second flexure zone can beconfigured to deflect in a radial direction from the axis of anelongated body 16 upon application of compression to the second flexurezone by a control wire. The second flexure zone can be configured tohave substantial elastic properties such that when the second flexurezone is not under compression it elastically returns to a preconfiguredshape which is radially deflected from the axis of the elongated body ina second direction.

In another embodiment multiple direction deflection of second flexurezone 34 is achieved with electrical initiation. As shown in FIG. 15control wires 40 a and 40 b are attached to a distal end of the secondflexure zone with solder joints 130 a and 130 b respectively. As withthe embodiment of FIG. 14C, in response to one of the control wires 40 aor 40 b pulling proximally on the distal end of the second flexure zone,the third tubular structure's laser-cut pattern biases deflection of thethird tubular structure in a plane approximately orthogonal to thespine. However, unlike in previously described embodiments, controlwires 40 a and 40 b pull on the distal end of the second flexure zonedue to electrically initiated shortening of the control wires ratherthan mechanically initiated tension along their length. As seen in FIG.15, control wires 40 a and 40 b also are attached to a proximal end ofthe second flexure zone via solder joints 130 a′ and 130 b′respectively. Unlike in the embodiment of FIG. 14C, the control wires 40a and 40 b do not extend proximal of the second flexure zone all the waythrough the elongated body 16 to handle assembly 200. Rather, electricalsupply wires 29 a and 29 b travel from handle 200 through the elongatedbody and are electrically connected to the control wire 40 a and 40 b atsolder joints 130 a and 130 a′, and 130 b and 130 b′ respectively.Actuator 260 of handle assembly 200 applies electrical current to supplyone of wires 29 a or 29 b, which transfers the electrical current to anelectrically connected control wire 40 a or 40 b. The control wire 40 aor 40 b, through which electrical current is passed, is shortened inresponse to the electrical current, which causes deflection of thesecond flexure zone 34.

In contrast to electrically initiated deflection, deflection via pullinga control wire (as in the embodiment shown in FIGS. 14A to 14C) involvesone or more control wires 40 a or 40 b extending all the way throughelongated shaft 16 from second flexure zone 34 to handle assembly 200.The elongated shaft 16 proximal to the second flexure zone is relativelyresistant to compression along its length so when tension is applied tothe control wire substantially only the second flexure zone 34 deflects.An elongated shaft 16 proximal to the second flexure zone that isconstructed to be resistant to compression may also be inherently stiffrelative to a shaft that does not need to resist compression.Furthermore, its stiffness may increase when it is resisting compressionapplied by a control wire under tension. Conversely, for electricallyinitiated deflection as in FIG. 15, since control wires 40 a and 40 bare positioned in the second flexure zone and do not extend all the waythrough the elongated body to the handle, the section of the elongatedbody 16 proximal to the second flexure zone is not under compressionwhen the control wires are shortened. Thus, the elongated shaft may befabricated in a manner that provides greater flexibility, which mayenhance deliverability and/or may reduce catheter whip during rotation.Electrically initiated control wire shape change or shortening may beutilized in conjunction with any of the previously described secondflexure zones 34 and control wires 40.

In one representative embodiment of electrically initiated deflection,flexure control element 40 a and 40 b comprises shape memory material,such as Nitinol wire. Electric current applied by supply wires 29 to theNitinol control wires resistively heats the Nitinol above itstransformation temperature causing the control wire to shorten, which inturn causes the second flexure zone to deflect. The control wire or thethird tubular structure 62 (which optionally may be resistively heatedvia supply wires 29) alternatively may comprise shape memory material,such as Nitinol with a heat-programmed bent shape, that pulls the secondflexure zone in the direction of the bend.

In another representative embodiment of electrically initiateddeflection, the control wires 40 a and 40 b comprise an electroactivepolymer, commonly referred to as an artificial muscle. Electricityapplied to the electroactive polymer control wire shortens the controlwire, causing the second flexure zone to deflect. When the electricityis turned off, the control wire resumes its initial shape, allowing thesecond flexure zone to straighten (or to be straightened).

The compressive and bending force and resulting directional bending fromthe deflection of the second flexure zone 34 has the consequence ofaltering the axial stiffness of the second flexure zone. The actuationof the control wire 40 serves to increase the axial stiffness of thesecond flexure zone. As will be described later, the axial stiffness ofthe deflected second flexure zone in combination with other flexibleaspects of the distal end region of the catheter treatment device allowsfor favorable performance in a renal artery neuromodulation treatment.

In terms of axial and torsional stiffnesses, the mechanical propertiesof second flexure zone 34 can, and desirably do, differ from themechanical properties of the first flexure zone 32. This is because thefirst flexure zone 32 and the second flexure zone 34 serve differentfunctions while in use.

The first flexure zone 32 transmits axial load and torque over a longerlength (L2) than the second flexure zone 34 (L3). Importantly, thesecond flexure zone 34 is also sized and configured to be deflectedremotely within the renal artery by the caregiver. In this arrangement,less resistance to deflection is desirable. This is a function that thefirst flexure zone 32 need not perform. Accordingly, the second flexurezone 34 is desirably sized and configured to be less stiff (when thecontrol wire 40 is not actuated) and, importantly, to possess greaterflexibility than the first flexure zone 32 in at least one plane ofmotion.

Still, because the second flexure zone 34, being distal to the firstflexure zone 32, precedes the first flexure zone 32 through the accessangle access angle α1, the second flexure zone 34 also includesmechanical properties that accommodate its flexure or bending at thepreferred access angle α1, without fracture, collapse, or significanttwisting of the elongated shaft 16.

The desired magnitude of axial stiffness, rotational stiffness, andflexibility for the second flexure zone 34 can be obtained by selectionof constituent material or materials to provide a desired elasticmodulus (expressed, e.g., in terms of a Young's Modulus (E)) indicativeof flexibility, as well as by selecting the construct and configurationof the second flexure zone 34, e.g., in terms of its interior diameter,outer diameter, wall thickness, and structural features, includingcross-sectional dimensions and geometry. Representative examples will bedescribed in greater detail later. Axial stiffness, torsional stiffness,and flexibility are properties that can be measured and characterized inconventional ways.

As before described, both the first and second flexure zones 32 and 34desirably include the mechanical properties of axial stiffnesssufficient to transmit to the thermal heating element 24 an axiallocating force. By pulling back on the handle assembly 200, axial forcesare transmitted by the force transmitting section 30 and the first andsecond flexure zones 32 and 34 to retract the thermal heating element 24in a proximal direction (away from the kidney) within the renal artery.Likewise, by pushing forward on the handle assembly 200, axial forcesare transmitted by the force transmitting section 30 and the first andsecond flexure zones 32 and 34 to advance the thermal heating element 24in a distal direction (toward the kidney) within the renal artery. Thus,proximal retraction of the distal end region 20 and thermal heatingelement 24 within the renal artery can be accomplished by the caregiverby manipulating the handle assembly 200 or shaft from outside theintravascular path 14.

As before described, both the first and second flexure zones 32 and 34also desirably include torsional strength properties that will allow thetransmission of sufficient rotational torque to rotate the distal endregion 20 of the treatment device 12 such that the thermal heatingelement 24 is alongside the circumference of the blood vessel wall whenthe second flexure zone 34 is deflected. By pulling or pushing on theactuator to deflect the thermal heating element 24 such that it achievesvessel wall contact, and then rotating the force transmitting section 30and, with it, the first and second flexure zones 32 and 34, the thermalheating element 24 can be rotated in a circumferential path within therenal artery. As described later, this rotating feature enables theclinical operator to maintain vessel wall contact as the thermal heatingelement 24 is being relocated to another treatment site. By maintainingwall contact in between treatments, the clinical operator is able toachieve wall contact in subsequent treatments with higher certainty inorientations with poor visualization.

4. Third Flexure Zone

As FIGS. 8A to 8D show, the distal end region 20 of the elongated shaft16 also optionally may include, distal to the optional second flexurezone 34, a third or distal flexure zone 44. In this arrangement, thelength L3 of the second flexure zone 34 may be shortened by a length L4,which comprises the length of the third flexure zone 44. In thisarrangement, the thermal heating element 24 is carried at the end of thethird flexure zone 44. It should be understood that the third flexurezone can be used interchangeably with distal flexure zone or forcedampening section or passively flexible structure or flexible tubularstructure.

As FIG. 8D shows, the third flexure zone 44 is sized, configured, andhas the mechanical properties that accommodate additional flexure orbending, independent of the first flexure zone 32 and the second flexurezone 34, at a preferred treatment angle α3. The distal flexure zone 44should also accommodate flexure sufficient for the distal end region 20to advance via a guide catheter into the renal artery withoutstraightening out the guide catheter or causing injury to the bloodvessel. The treatment angle α3 provides for significant flexure aboutthe axis of the distal end region 20 (a representative embodiment isshown in FIG. 18C). Not under the direct control of the physician,flexure at the third flexure zone occurs in response to contact betweenthe thermal heating element 24 and wall tissue occasioned by the radialdeflection of the thermal heating element 24 at the second flexure zone34 (see FIG. 6B). Passive deflection of the third flexure zone providesthe clinical operator with visual feedback via fluoroscopy or otherangiographic guidance of vessel wall contact (as shown in FIGS. 28A to28E). Additionally, the third flexure zone desirably orients the regionof tissue contact along a side of the thermal heating element 24,thereby increasing the area of contact. The third flexure zone 44 alsobiases the thermal heating element 24 against tissue, therebystabilizing the thermal heating element 24.

The function of the third flexure zone 44 provides additional benefitsto the therapy. As actuation of the control wire 40 deflects the secondflexure zone 34, pressing the thermal heating element 24 against aninner wall of a renal artery the third flexure zone 44 effectivelydampens the contact force between the thermal heating element 24 and thevessel wall. This effect is particularly valuable in a renal arterytreatment due to movement of the renal artery caused by respirationand/or pulsatile flow. While the flexibility of the proximal flexurezone allows the distal end region of the treatment catheter to followmovement of the renal artery during respiration, the increased axialstiffness of the deflected second or intermediate flexure zone provideshelpful integrity to the distal end region to maintain contact betweenthe thermal heating element and vessel wall. The third or distal flexurezone helps soften or cushion the contact force so that atraumaticcontact can be achieved and maintained, particularly during movement ofthe renal artery. By dampening this contact force, the third flexurezone minimizes the chance of mechanical injury to the vessel wall andavoids excessive contact between the thermal heating element and vesselwall (see discussion of active surface area).

As FIG. 8A shows, the third flexure zone 44 is desirably sized andconfigured in length L4 to be less than length L3. This is because, interms of length, the distance required for orienting and stabilizing thethermal heating element 24 in contact with a wall of the renal artery issignificantly less than the distance required for radially deflectingthe thermal heating element 24 within the renal artery. In someembodiments, length L4 can be less than or equal to about 1 cm. In otherembodiments, the length L4 is from about 2 mm to about 5 mm. In onerepresentative embodiment, the length L4 is less than or equal to about5 mm. In another representative embodiment, the length L4 is less thanor equal to about 2 mm. In another representative embodiment wherein thesecond flexure zone 34 is comprised of a hinge joint, the length L4 isless than or equal to about 16 mm which, in this embodiment, can begreater than the length L3 of the second flexure zone 34.

When the catheter is outside the patient and the third flexure zone 44is in a substantially straight, non-deflected configuration, treatmentangle α3 (as shown in FIG. 8D) is approximately 180°. Upon fulldeflection of the third flexure zone 44, the angle α3 is reduced toanywhere between about 45° and 180°. In a representative embodiment,upon full deflection, angle α3 is about 75° to about 135°. In anotherrepresentative embodiment, upon full deflection, angle α3 is less thanor equal to about 90°.

In the passively deflected configuration of FIG. 8D, the third flexurezone 44 comprises a radius of curvature RoC₃. In embodiments where thecurvature of third flexure zone 44 does not vary or is consistent alongthe length L4, the length L4 and the contact angle α3 may define theradius of curvature RoC₃. It should be understood that the curvature ofthird flexure zone 44, and thereby the radius of curvature RoC₃ of thethird flexure zone, alternatively may vary along the length L4.

In such embodiments where the curvature does not vary, the length L4 maydefine a fraction (180°−α3)/360° of the circumference C₃ of a circlewith an equivalent radius of curvature RoC₃. Thus, the circumference ofsuch an equivalent circle is:

$\begin{matrix}\begin{matrix}{C_{3} = {\frac{360{^\circ}}{\left( {{180{^\circ}} - {\alpha 3}} \right)} \times L\; 4}} \\{= {2\pi \times {RoC}_{3}}}\end{matrix} & (14)\end{matrix}$

Solving for the radius of curvature RoC₂:

$\begin{matrix}{{RoC}_{3} = \frac{360{^\circ} \times L\; 4}{2\pi \times \left( {{180{^\circ}} - {\alpha 3}} \right)}} & (15)\end{matrix}$

Thus, in a representative embodiment of the third flexure zone 44 wherethe curvature of the third flexure zone does not vary along the lengthL4, where the length L4 is about 2 mm to about 5 mm, and where thecontact angle α3 is about 75° to about 135°, the radius of curvatureRoC₃ is about 1 mm to about 6 mm.

As will be apparent, Equation (15) may be rearranged such that thelength L4 and the radius of curvature RoC₃ define the contact angle α3.Furthermore, Equation (15) may be rearranged such that the radius ofcurvature RoC₃ and the angle α3 define the length L4. Thus, inembodiments where the curvature of third flexure zone 44 does not varyalong the length L4, any one of the length L4, angle α3 and radius ofcurvature RoC₃ may be specified by specifying the other two variables.

The mechanical properties of third flexure zone 44 and the secondflexure zone 34 in terms of axial stiffness, torsional stiffness, andflexibility can be comparable. However, the third flexure zone 44 can besized and configured to be less stiff and, importantly, to possessgreater flexibility than the second flexure zone 34.

In the embodiment just described (and as shown in FIG. 8D), the distalend region 20 may comprise a first or proximal flexure zone 32, a secondor intermediate flexure zone 34, and a third or distal flexure zone 44.The first, second and third flexure zones function independently fromeach other, so that the distal end region 20 of the elongated shaft 16can, in use, be placed into a more compound, complex, multi-bendstructure 36. The compound, complex, multi-bend structure 36 comprises afirst deflection region at the access angle α1 over a length L2 (thefirst flexure zone 32); an second deflection region at the contact angleα2 over a length L3 (the second flexure zone 34); and a third deflectionregion at the treatment angle α3 over a length L4 (the third flexurezone 44). In the compound, complex, multi-bend structure 36, all lengthsL2, L3, and L4 and all angles α1, α2, and α3 can differ. This is becausethe angle α1 and length L2 are specially sized and configured to gainaccess from an aorta into a respective renal artery through a femoralartery access point; the angle α2 and length L3 are specially sized andconfigured to align a thermal heating element 24 element with aninterior wall inside the renal artery; and the angle α3 and length L4are specially sized and configured to optimize surface contact betweentissue and the thermal heating element/heat transfer element.

The composite length of L2, L3 and L4 of the first, second and thirdflexure zones, respectively, of the distal end region 20, along with thelength L1 of the force transmitting section 30 and the length L5 (seeFIG. 9A) of the thermal heating element 24 (i.e., the composite lengthequal to L1+L2+L3+L4+L5), specifies a working length of the elongatedshaft 16 of the treatment device 12. In some representative embodiments,this working length is about 40 cm to about 125 cm. In a representativeembodiment where no guide catheter is used, then this working length maybe about 40 cm to about 50 cm. If, alternatively, a 55 cm length guidecatheter is used, then this working length may be about 70 cm to about80 cm. If a 90 cm length guide catheter is used, then this workinglength may be about 105 cm to about 115 cm.

As shown in FIGS. 20A to 20C, third flexure zone can optionally includea force redirecting element 49 which is sized and configured to promotebuckling or bending in the first and/or second flexure zones withreduced vessel wall contact force. This can reduce a risk of traumaduring advancement of the distal end region 20 in to a renal artery,facilitate navigation through tortuous vessels, and facilitate placementof a thermal element 24 in contact with an inner wall of a renal artery.Force redistribution element 49 distances a thermal element 24 on thedistal tip of an elongated body 16 from an axis of the elongated body byabout 1 mm to 4 mm and is located within the distal 4 mm to 10 mm of theelongated body. For example the force redirecting element 49 comprise abend in a third flexure zone of about 15° to 45° (e.g. 30°). Applicantshave previously described force redirecting elements. See, for exampleApplicants' U.S. patent application Ser. No. 12/790,639 filed on May 28,2010 which is incorporated herein by reference in its entirety.

C. Size and Configuration of the Thermal Heating Element for AchievingNeuromodulation in a Renal Artery

In some patients, it may be desirable to create multiple focal lesionsthat are circumferentially spaced along the longitudinal axis of therenal artery. However, it should be understood that a single focallesion with desired longitudinal and/or circumferential dimensions, oneor more full-circle lesions, multiple circumferentially spaced focallesions at a common longitudinal position, and/or multiplelongitudinally spaced focal lesions at a common circumferential positionalternatively or additionally may be created.

Creating multiple focal lesions that are circumferentially spaced alongthe longitudinal axis of the renal artery avoids the creation of afull-circle lesion, thereby reducing a risk of vessel stenosis, whilestill providing the opportunity to circumferentially treat the renalplexus, which is distributed about the renal artery. It is desirable foreach lesion to cover at least 10% of the vessel circumference toincrease the probability of affecting the renal plexus. However, it isimportant that each lesion not be too large (e.g., >60% of vesselcircumference) lest the risk of a stenotic effect increases (or otherundesirable healing responses such as thrombus formation or collateraldamage). In one embodiment the energy delivery element 24 is configuredto create a lesion at least 30% (i.e. greater than or equal to 30%) ofthe vessel circumference. In another embodiment, the energy deliveryelement 24 is configured to create a lesion of greater than or equal to30% but less than 60% of the vessel circumference. It is also importantthat each lesion be sufficiently deep to penetrate into and beyond theadventitia to thereby affect the renal plexus. However, lesions that aretoo deep (e.g., >5 mm) run the risk of interfering with non-targettissue and tissue structures (e.g., renal vein) so a controlled depth ofthermal treatment is desirable.

As described in greater detail below, thermal heating element 24 may bedelivered to a first treatment site within the renal artery such thatthe thermal heating element 24 is positioned in contact with an interiorwall of the artery for treating the renal plexus (see FIG. 25). Oncepositioned within the artery as desired, energy may be delivered via thethermal heating element to create a first focal lesion at this firsttreatment site (see FIG. 25). The first focal lesion creates a firsttreatment zone 98 a that is not continuous completely around thecircumference of the renal artery in a radial plane or cross-sectionnormal to the wall or to the longitudinal axis of the artery (i.e., thefirst focal lesion does not extend all the way around the circumferenceof the vessel wall). As a result, there is a discrete untreated zoneabout the circumference of the artery in the radial plane of the firsttreatment zone normal to the longitudinal axis of the artery.

After formation of the first focal lesion at the first treatment zone 98a, the thermal heating element 24 optionally may be angularlyrepositioned relative to the renal artery (see FIGS. 24E and 24F). Thisangular repositioning may be achieved, for example, by angularlyrotating the elongated shaft 16 of treatment device 12 via handleassembly 200 (see FIG. 19A). In addition to angular repositioning of thethermal heating element 24, the thermal heating element optionally maybe repositioned along the lengthwise or longitudinal dimension of therenal artery (see FIG. 24E). This longitudinal repositioning may beachieved, for example, by translating the elongated shaft 16 oftreatment device 12 via handle assembly 200, and may occur before, afteror concurrent with angular repositioning of the thermal heating element24.

Repositioning the thermal heating element 24 in both the longitudinaland angular dimensions places the thermal heating element in contactwith the interior wall of the renal artery at a second treatment sitefor treating the renal plexus (see FIG. 24E). Energy then may bedelivered via the thermal heating element to form a second focal lesionat this second treatment site, thereby creating a second treatment zone98 b and a second untreated zone (see FIG. 24F).

As with the first treatment zone created by the first focal lesion, thesecond treatment zone is not continuous about the complete circumferenceof the renal artery. However, the first and second treatment zones (aswell as the first and second untreated zones) are angularly andlongitudinally offset from one another about the angular and lengthwisedimensions of the renal artery, respectively (see FIG. 24G).Superimposing the first and second treatment zones, which are positionedalong different cross-sections or radial planes of the renal artery,about a common cross-section provides a composite treatment zone thatcovers a greater portion of the circumference of the artery than eithertreatment zone individually. As this composite treatment zone is notcontinuous (i.e., it is formed from multiple, longitudinally andangularly spaced treatment zones), it is expected that a greater portionof the circumference of the arterial wall may be treated with reducedrisk of vessel stenosis, as compared to formation of a single focallesion covering an equivalent portion of the arterial circumference at asingle treatment site (i.e., at a single lengthwise position or about asingle cross-section of the renal artery).

One or more additional focal lesions optionally may be formed at one ormore additional angularly and longitudinally spaced treatment sites tocreated additional angularly and longitudinally spaced treatment zones(see FIGS. 24G-24K). In one representative embodiment, superimpositionof all or a portion of the treatment zones provides a compositetreatment zone that is non-continuous (i.e., that is broken up along thelengthwise dimension or longitudinal axis of the renal artery), yet thatis substantially circumferential (i.e., that substantially extends allthe way around the circumference of the renal artery over a lengthwisesegment of the artery). This superimposed treatment zone beneficiallydoes not create a continuous circumferential lesion along any individualradial plane or cross-section normal to the artery, which may reduce arisk of acute or late stenosis formation, as compared to circumferentialtreatments that create such continuous circumferential lesions.

Non-continuous circumferential treatment by positioning thermal heatingelement(s) at different angular orientations along multiple lengthwiselocations may preferentially affect anatomical structures thatsubstantially propagate along the lengthwise dimension of the artery.Such anatomical structures can be neural fibers and/or structures thatsupport the neural fibers (e.g., the renal plexus). Furthermore, suchnon-continuous circumferential treatment may mitigate or reducepotentially undesirable effects induced in structures that propagateabout the angular dimension of the artery, such as smooth muscle cells.Were a continuous circumferential lesion alternatively to be formed, theangular or circumferential orientation of the smooth muscle cellsrelative to the artery may increase a risk of acute or late stenosis oracute vessel spasm.

In multi-thermal heating element configurations (e.g., multi-electrodeconfigurations), such as in FIG. 7B, multiple non-continuouscircumferential treatment zones can be created during a single catheterplacement within the renal artery. The multiple thermal heating elementscan be spaced and located such that they are longitudinally andangularly spaced apart from one another and such that they createlongitudinally offset and angularly opposed or offset treatment zones.Retraction and rotation of the treatment device 12 can reposition thethermal heating elements to create additional longitudinally andangularly separated treatment zones, thereby allowing the practitionerthe ability to create multiple treatment zones per catheter placementand several treatment zones via only two catheter placements.

As described (and as FIG. 9A shows), the thermal heating element 24 issized and configured, in use, to contact an internal wall of the renalartery. In the illustrated embodiment (see FIG. 9A), the thermal heatingelement 24 takes the form of an electrode 46 sized and configured toapply an electrical field comprising radiofrequency (RF) energy from thegenerator 26 to a vessel wall. In the illustrated embodiment, theelectrode 46 is operated in a monopolar or unipolar mode. In thisarrangement, a return path for the applied RF electric field isestablished, e.g., by an external dispersive electrode (shown as 38 inFIG. 6A), also called an indifferent electrode or neutral electrode. Themonopolar application of RF electric field energy serves to ohmically orresistively heat tissue in the vicinity of the electrode 46. Theapplication of the RF electrical field thermally injures tissue. Thetreatment objective is to thermally induce neuromodulation (e.g.,necrosis, thermal alteration or ablation) in the targeted neural fibers.The thermal injury forms a lesion in the vessel wall, which is shown,e.g., in FIG. 10B. Alternatively, a RF electrical field can be deliveredwith an oscillating intensity that does not thermally injure the tissuewhereby neuromodulation in the targeted nerves is accomplished byelectrical modification of the nerve signals.

The active surface area of contact (ASA) between the thermal element 24or electrode 46 and the vessel wall has great bearing on the efficiencyand control of the transfer of a thermal energy field across the vesselwall to thermally affect targeted neural fibers in the renal plexus(RP). The active surface area of the thermal element 24 or electrode 46is defined as the energy transmitting area of the thermal element 24 orelectrode 46 that can be placed in intimate contact against tissue. Toomuch contact between the thermal element and the vessel wall and/or toomuch power may create unduly high temperatures at or around theinterface between the tissue and the thermal element, thereby creatingexcessive heat generation at this interface and/or spasm and contractionof the vessel wall. This excessive heat can also create a lesion that iscircumferentially too large, increasing the risk of stenosis. Thisexcessive heat can also lead to undesirable thermal damage at the vesselwall, which stiffens and desiccates the vessel tissue making it moresusceptible to puncture and perforation. Additionally, the tissuedesiccation (i.e., dehydration) reduces the electrical and thermalconductivity of the tissue. Reduced conductivity may potentially createa lesion that is too shallow to reach the neural fibers and may alsoresult in the buildup of excessive heat, causing increased andundesirable damage to the vessel wall and increasing the likelihood ofthrombus formation. Although the risks of excessive wall contact andheating are many, too little contact between the thermal element and thevessel wall may impair the efficacy of the treatment. For example, toolittle contact may result in superficial heating of the vessel wall,thereby creating a lesion that is too small (e.g., <10% of vesselcircumference) and/or too shallow to reach the target renal neuralfibers.

While the active surface area (ASA) of the thermal heating element 24and electrode 46 is important to creating lesions of desirable size anddepth, the ratio between the active surface area (ASA) and total surfacearea (TSA) of the thermal heating element 24 and electrode 46 is alsoimportant. The ASA to TSA ratio influences lesion formation in two ways:(1) the degree of resistive heating via the electric field, and (2) theeffects of blood flow or other convective cooling elements such asinjected or infused saline. As discussed above, the RF electric fieldcauses lesion formation via resistive heating of tissue exposed to theelectric field. The higher the ASA to TSA ratio (i.e., the greater thecontact between the electrode and tissue), the greater the resistiveheating. As discussed in greater detail below, the flow of blood overthe exposed portion of the electrode (TSA-ASA) provides conductive andconvective cooling of the electrode, thereby carrying excess thermalenergy away from the interface between the vessel wall and electrode. Ifthe ratio of ASA to TSA is too high (e.g., 50%), resistive heating ofthe tissue can be too aggressive and not enough excess thermal energy isbeing carried away, resulting in excessive heat generation and increasedpotential for stenotic injury, thrombus formation and undesirable lesionsize. If the ratio of ASA to TSA is too low (e.g., 10%), then there istoo little resistive heating of tissue, thereby resulting in superficialheating and smaller and shallower lesions.

Various size constraints for the thermal heating element 24 may beimposed for clinical reasons by the maximum desired dimensions of theguide catheter, as well as by the size and anatomy of the renal arteryitself. Typically, the maximum outer diameter (or cross-sectionaldimension for non-circular cross-section) of the electrode 46 comprisesthe largest diameter encountered along the length of the elongated shaft16 distal to the handle assembly 200. Thus, the outer diameters of theforce transmitting section 30 and proximal, intermediate and distalflexure zones 32, 34, and 44 are equal to or (desirably) less than themaximum outer diameter of the electrode 46.

In a representative embodiment shown in FIG. 9A, the electrode 46 takesthe form of a right circular cylinder, possessing a length L5 that isgreater than its diameter. The electrode 46 further desirably includes adistal region that is rounded to form an atraumatic end surface 48. Inthe representative embodiment shown in FIG. 9B, the electrode 46 isspherical in shape, such that the length L5 is equal to the electrode'sdiameter. The spherical shape, too, presents an atraumatic surface tothe tissue interface.

As shown in FIGS. 9A and 9B, the angle α3 and length L4 of the distalflexure zone 44 are specially sized and configured, given the TSA of therespective electrode, to optimize an active surface area of contactbetween tissue and the respective electrode 46 (ASA). The angle α3 andthe length L4 of the distal flexure zone 44 make it possible todesirably lay at least a side quadrant 50 of the electrode 46 againsttissue (see FIG. 9C), though it should be understood that the electrode46 does not necessarily need to be positioned with its side quadrant 50against tissue prior to power delivery. In a representative embodiment,the active surface area of the electrode 46 contacting tissue (ASA) canbe expressed as ASA≧0.25 TSA and ASA≦0.50 TSA.

An ASA to TSA ratio of over 50% may be effective with a reduced powerdelivery profile. Alternatively, increasing the convective cooling ofthe electrode that is exposed to blood flow can compensate for a higherASA to TSA ratio. As discussed further below, this could be achieved byinjecting or infusing cooling fluids such as saline (e.g., roomtemperature saline or chilled saline) over the electrode and into theblood stream.

The stiffnesses of each of the second and third flexure zones 34 and 44are also selected to apply via the electrode a stabilizing force thatpositions the electrode 46 in substantially secure contact with thevessel wall tissue. This stabilizing force also influences the amount ofwall contact achieved by the thermal heating element (i.e., the ASA toTSA ratio). With greater stabilizing force, the thermal heating elementhas more wall contact and with less stabilizing force, less wall contactis achieved. Additional advantages of the stabilizing force include, (1)softening the contact force between the distal end 20 and vessel wall tominimize risk of mechanical injury to vessel wall, (2) consistentpositioning of the electrode 46 flat against the vessel wall, and (3)stabilizing the electrode 46 against the vessel wall. As discussed abovewith respect to the combined effect of the first/proximal flexure zoneand second/intermediate flexure zone, this stabilizing force allows thecatheter treatment device to maintain consistent contact with the vesselwall even during motion of the renal artery during respiration. Thestabilizing force also allows the electrode to return to a neutralposition after the electrode is removed from contact with the wall.

As previously discussed, for clinical reasons, the maximum outerdiameter (or cross-sectional dimension) of the electrode 46 isconstrained by the maximum inner diameter of the guide catheter throughwhich the elongated shaft 16 is to be passed through the intravascularpath 14. Assuming that an 8 French guide catheter 94 (which has an innerdiameter of approximately 0.091 inches) is, from a clinical perspective,the largest desired catheter to be used to access the renal artery, andallowing for a reasonable clearance tolerance between the electrode 46and the guide catheter, the maximum diameter of the electrode 46 isconstrained to about 0.085 inches. In the event a 6 French guidecatheter is used instead of an 8 French guide catheter, then the maximumdiameter of the electrode 46 is constrained to about 0.070 inches. Inthe event a 5 French guide catheter is used, then maximum diameter ofthe electrode 46 is constrained to about 0.053 inches. Based upon theseconstraints and the aforementioned power delivery considerations, theelectrode 46 desirably has a maximum outer diameter of from about 0.049to about 0.051 inches. The electrode 46 also desirably has a minimumouter diameter of about 0.020 inches to provide sufficient cooling andlesion size. In some embodiments, the electrode 46 (i.e., the thermalheating element 24) may have a length of about 1 mm to about 3 mm. Insome embodiments in which the thermal heating element is a resistiveheating element, it can have a maximum outer diameter from about 0.049to 0.051 inches and a length of about 10 mm to 30 mm.

D. Applying Energy to Tissue Via the Thermal Heating Element

Referring back to FIG. 5, in the illustrated embodiment, the generator26 may supply to the electrode 46 a pulsed or continuous RF electricfield. Although a continuous delivery of RF energy is desirable, theapplication of thermal energy in pulses may allow the application ofrelatively higher energy levels (e.g., higher power), longer or shortertotal duration times, and/or better controlled intravascular renalneuromodulation therapy. Pulsed energy may also allow for the use of asmaller electrode.

The thermal therapy may be monitored and controlled, for example, viadata collected with one or more sensors 52, such as temperature sensors(e.g., thermocouples, thermistors, etc.), impedance sensors, pressuresensors, optical sensors, flow sensors, chemical sensors, force sensors,strain sensors, etc. (see FIGS. 10A and 10B). Sensor(s) 52 may beincorporated into or on electrode 46 and/or in/on adjacent areas on thedistal end region 20.

Advantageously, since the second flexure zone 34 deflects in acontrolled manner, the surface of electrode 46 that contacts tissueduring treatment may be known. As such, sensor(s) 52 may be incorporatedinto the electrode in a manner that specifies whether the sensor(s) arein contact with tissue at the treatment site and/or are facing bloodflow. The ability to specify sensor placement relative to tissue andblood flow is highly significant, since a temperature gradient acrossthe electrode from the side facing blood flow to the side in contactwith the vessel wall may be up to about 15° C. Significant gradientsacross the electrode in other sensed data (e.g., flow, pressure,impedance, etc.) also are expected.

The sensor(s) 52 may, for example, be incorporated on the side of theelectrode that contacts the vessel wall at the treatment site duringpower and energy delivery (see FIG. 10B), may be incorporated into thetip of the electrode, may be incorporated on the opposing side of theelectrode that faces blood flow during energy delivery (see FIG. 10A),and/or may be incorporated within certain regions of the electrode(e.g., distal, proximal, quandrants, etc.). In some embodiments,multiple sensors may be provided at multiple positions along theelectrode and/or relative to blood flow. For example, a plurality ofcircumferentially and/or longitudinally spaced sensors may be provided.In one embodiment, a first sensor may contact the vessel wall duringtreatment, and a second sensor may face blood flow.

Additionally or alternatively, various microsensors can be used toacquire data corresponding to the thermal heating element, the vesselwall and/or the blood flowing across the thermal heating element. Forexample, arrays of micro thermocouples and/or impedance sensors can beimplemented to acquire data along the thermal heating element or otherparts of the treatment device. Sensor data can be acquired or monitoredprior to, simultaneous with, or after the delivery of energy or inbetween pulses of energy, when applicable. The monitored data may beused in a feedback loop to better control therapy, e.g., to determinewhether to continue or stop treatment, and it may facilitate controlleddelivery of an increased or reduced power or a longer or shorterduration therapy.

Non-target tissue may be protected by blood flow (F) within therespective renal artery that serves as a conductive and/or convectiveheat sink that carries away excess thermal energy. For example (as FIGS.10A and 10B show), since blood flow (F) is not blocked by the elongatedshaft 16 and the electrode 46 it carries, the native circulation ofblood in the respective renal artery serves to remove excess thermalenergy from the non-target tissue and the thermal heating element. Theremoval of excess thermal energy by blood flow also allows fortreatments of higher power, where more power can be delivered to thetarget tissue as thermal energy is carried away from the electrode andnon-target tissue. In this way, intravascularly-delivered thermal energyheats target neural fibers located proximate to the vessel wall tomodulate the target neural fibers, while blood flow (F) within therespective renal artery protects non-target tissue of the vessel wallfrom excessive or undesirable thermal injury. When energy is deliveredin pulses, the time interval between delivery of thermal energy pulsesmay facilitate additional convective or other cooling of the non-targettissue of the vessel wall compared to applying an equivalent magnitudeor duration of continuous thermal energy.

It may also be desirable to provide enhanced cooling by inducingadditional native blood flow across the thermal heating element. Forexample, techniques and/or technologies can be implemented by thecaregiver to increase perfusion through the renal artery or to thethermal heating element itself. These techniques include positioningpartial occlusion elements (e.g., balloons) within upstream vascularbodies such as the aorta or proximal portion of the renal artery toimprove flow across the thermal heating element.

In addition, or as an alternative, to passively utilizing blood flow (F)as a heat sink, active cooling may be provided to remove excess thermalenergy and protect non-target tissues. For example, a thermal fluidinfusate may be injected, infused, or otherwise delivered into thevessel in an open circuit system. Additionally or alternatively, thethermal heating element 24 (e.g., electrode 46) may be actively cooledin a closed circuit system (i.e., without delivering any agents into thebloodstream) to remove excess thermal energy, such as by circulating athermal fluid infusate (e.g., a cryogenic or chilled fluid) within thedistal end region 20 or by some other mechanism.

Thermal fluid infusates used for active cooling may, for example,comprise (room temperature or chilled) saline or some otherbiocompatible fluid. The thermal fluid infusate(s) may, for example, beintroduced through the treatment device 12 via one or more infusionlumens and/or ports. When introduced into the bloodstream, the thermalfluid infusate(s) may, for example, be introduced through a guidecatheter at a location upstream from the thermal heating element 24 orelectrode 46, or at other locations relative to the tissue for whichprotection is sought. The delivery of a thermal fluid infusate in thevicinity of the treatment site (via an open circuit system and/or via aclosed circuit system) may, for example, allow for the application ofincreased/higher power, may allow for the maintenance of lowertemperature at the vessel wall during energy delivery, may facilitatethe creation of deeper or larger lesions, may facilitate a reduction intreatment time, may allow for the use of a smaller electrode size, or acombination thereof.

As seen in FIG. 11A, electrode 46 may comprise an open circuit systemhaving an irrigated electrode with at least one port 47 that is coupledto a lumen in fluid communication with a source of infusate and apumping mechanism (e.g., manual injection or a motorized pump) forinjection or infusion of saline or some other biocompatible thermalfluid infusate I from outside the patient, through elongated shaft 16and through the electrode 46 into the patient's bloodstream duringenergy delivery. In an alternative closed circuit embodiment, such asthat seen in FIG. 11B, the lumen 45 may, for example, comprise a supplylumen 45 a and a return lumen 45 b that may be utilized to circulate thethermal fluid infusate I near or through the electrode 46 to removeexcess thermal energy without releasing the fluid into the bloodstream.The thermal fluid acts as a convective and conductive heat sink thatcools the electrode and/or the vessel wall during power and energydelivery.

In FIG. 11A, the electrode 46 illustratively comprises six ports 47 thatare spaced roughly equidistant about the circumference of the electrode,but it should be understood that any alternative number of ports 47 (forexample, any alternative number of ports 47 in the range of about oneport to about twelve ports) and/or any alternative spacing of the ports47 about the circumference of the electrode 46 alternatively may beprovided. For example, in one alternative embodiment, a single port 47may be provided on the side of the electrode that contacts the vesselwall for injection or infusion of saline directly at the treatment site.

Although many of the embodiments described herein pertain to electricalsystems configured for the delivery of RF energy, it is contemplatedthat the desired treatment can be accomplished by other means, e.g., bycoherent or incoherent light; direct thermal modification (e.g., with aheated or cooled fluid or resistive heating element); microwave;ultrasound (including high intensity focused ultrasound); diode laser;radiation; a tissue heating fluid; and/or a cryogenic fluid.

III. REPRESENTATIVE EMBODIMENTS A. First Representative Embodiment(First Flexure Zone, Second Flexure Zone with a Centrally PositionedSpine, and Third Flexure Zone with Distally Carried Thermal HeatingElement)

FIGS. 12A to 18H show a representative embodiment of an elongated shaft16 that includes a proximal force transmitting section 30, as well asfirst, second and third flexure zones 32, 34, and 44, having thephysical and mechanical features described above. In this embodiment,the thermal heating element 24 is carried distally of the third flexurezone 44 (see, e.g., FIG. 13A).

1. Force Transmitting Section

In the illustrated embodiment, as shown in FIGS. 12A and 12B, theproximal force transmitting section 30 comprises a first elongated anddesirably tubular structure, which can take the form of, e.g., a firsttubular structure 54. The first tubular structure 54 is desirably a hypotube that is made of a metal material, e.g. of stainless steel, or ashape memory alloy, e.g., nickel titanium (a.k.a., Nitinol or NiTi), topossess the requisite axial stiffness and torsional stiffness, asalready described, for the force transmitting section 30. As alreadydescribed, the force transmitting section 30 comprises the most stiffsection along the elongated shaft 16, to facilitate axially movement ofthe elongated shaft 16, as well as rotational manipulation of theelongated shaft 16 within the intravascular path 14. Alternatively, thefirst tubular structure 54 may comprise a hollow coil, hollow cable,solid cable (w/ embedded wires), a braided or braid reinforced shaft, acoil reinforced polymer shaft, a metal/polymer composite, etc.

The stiffness is a function of material selection as well as structuralfeatures such as interior diameter, outside diameter, wall thickness,geometry and other features that are made by micro-engineering,machining, cutting and/or skiving the hypo tube material to provide thedesired axial and torsional stiffness characteristics. For example, theelongated shaft can be a hypo tube that is laser cut to various shapesand cross-sectional geometries to achieve the desired functionalproperties.

When the first tubular structure 54 is made from an electricallyconductive metal material, the first tubular structure 54 may include asheath 56 or covering made from an electrically insulating polymermaterial or materials, which is placed over the outer diameter of theunderlying tubular structure. The polymer material can also be selectedto possess a desired durometer (expressing a degree of stiffness or lackthereof) to contribute to the desired overall stiffness of the firsttubular structure 54. Candidate materials for the polymer materialinclude, but are not limited to, polyethylene terephthalate (PET);Pebax® material; nylon; polyurethane, Grilamid® material or combinationsthereof. The polymer material can be laminated, dip-coated,spray-coated, or otherwise deposited/attached to the outer diameter ofthe tube.

2. First Flexure Zone

As FIGS. 13A, 13B, and 13C show, the first or proximal flexure zone 32comprises a second elongated and desirably tubular structure, which cantake the form of, e.g., a second tubular structure 58. The secondtubular structure 58 can be made from the same or different material asthe first tubular structure 54. The axial stiffness and torsionalstiffness of the second tubular structure 58 possesses the requisiteaxial stiffness and torsional stiffness, as already described, for thefirst flexure zone 32. As already described, the first flexure zone 32may be less stiff and more flexible than the force transmitting section30, to navigate the severe bend at and prior to the junction of theaorta and respective renal artery. The second tubular structure isdesirably a hypo tube, but can alternatively comprise a hollow coil,hollow cable, braided shaft, etc.

It may be desirable for the first and second tubular structures 54 and58 to share the same material. In this event, the form and physicalfeatures of the second tubular structure 58 may be altered, compared tothe first tubular structure 54, to achieve the desired stiffness andflexibility differences. For example, the interior diameter, outsidediameter, wall thickness, and other engineered features of the secondtubular structure 58 can be tailored to provide the desired axial andtorsional stiffness and flexibility characteristics. For example, thesecond tubular structure 58 can be laser cut along its length to providea bendable, spring-like structure. Depending on the ease ofmanufacturability the first and second tubular structures may beproduced from the same piece of material or from two separate pieces. Inthe event the first tubular structure and second tubular structure arenot of the same material, the outside diameter of the second tubularstructure 58 can be less than the outer diameter of first tubularstructure 54 (or have a smaller wall thickness) to create the desireddifferentiation in stiffness between the first and second tubularstructures 54 and 58.

When the second tubular structure 58 is made from an electricallyconductive metal material, the second tubular structure 58, like thefirst tubular structure 54, includes a sheath 60 (see FIGS. 13B and 13C)or covering made from an electrically insulating polymer material ormaterials, as already described. The sheath 60 or covering can also beselected to possess a desired durometer to contribute to the desireddifferentiation in stiffness and flexibility between the first andsecond tubular structures 58.

The second tubular structure 58 can comprise a different material thanthe first tubular structure 54 to impart the desired differentiation instiffness and flexibility between the first and second tubularstructures 58. For example, the second tubular structure 58 can comprisea cobalt-chromium-nickel alloy, instead of stainless steel.Alternatively, the second tubular structure 58 can comprise a less rigidpolymer, a braided or braid-reinforced shaft, a coil reinforced polymershaft, a metal/polymer composite, nitinol or hollow cable-likestructure. In addition to material selection, the desireddifferentiation in stiffness and overall flexibility can be achieved byselection of the interior diameter, outside diameter, wall thickness,and other engineered features of the second tubular structure 58, asalready described. Further, a sheath 60 or covering made from anelectrically insulating polymer material, as above described, can alsobe placed over the outer diameter of the second tubular structure 58 toimpart the desired differentiation between the first and second tubularstructures 54 and 58.

3. Second Flexure Zone

As FIGS. 14A, 14B, and 14C show, the second or intermediate flexure zone34 comprises a third elongated and desirably tubular structure, whichcan take the form of, e.g., a third tubular structure 62. The thirdtubular structure 62 can be made from the same or different material asthe first and/or second tubular structures 54 and 58. The axialstiffness and torsional stiffness of the third tubular structure 62possesses the requisite axial stiffness and torsional stiffness, asalready described, for the second flexure zone 34. As already described,the second flexure zone 34 may be less stiff and more flexible than thefirst flexure zone 32, to facilitate controlled deflection of the secondflexure zone 34 within the respective renal artery.

If the second and third tubular structures 58 and 62 share the samematerial, the form and physical features of the third tubular structure62 are altered, compared to the second tubular structure 58, to achievethe desired stiffness and flexibility differences. For example, theinterior diameter, outside diameter, wall thickness, and otherengineered features of the third tubular structure 62 can be tailored toprovide the desired axial and torsional stiffness and flexibilitycharacteristics. For example, the third tubular structure 62 can belaser cut along its length to provide a more bendable, more spring-likestructure than the second tubular structure 58.

When the third tubular structure 62 is made from an electricallyconductive metal material, the third tubular structure 62 also mayinclude a sheath 64 (see FIG. 14C) or covering made from an electricallyinsulating polymer material or materials, as already described. Thesheath 64 or covering can also be selected to possess a desireddurometer to contribute to the desired differentiation in stiffness andflexibility between the second and third tubular structure 62.

The third tubular structure 62 can comprise a different material thanthe second tubular structure to impart the desired differentiation instiffness and flexibility between the second and third tubularstructures 62. For example, the third tubular structure 62 can include aNitinol material, to impart the desired differentiation in stiffnessbetween the second and third tubular structures 58 and 62. In additionto material selection, the desired differentiation in stiffness andoverall flexibility can be achieved by selection of the interiordiameter, outside diameter, wall thickness, and other engineeredfeatures of the third tubular structure 62, as already described.

For example, in diameter, the outside diameter of the third tubularstructure 62 is desirably less than the outer diameter of second tubularstructure 58. Reduction of outside diameter or wall thickness influencesthe desired differentiation in stiffness between the second and thirdtubular structures 58 and 62.

As discussed in greater detail above, preferential deflection of thesecond flexure zone is desirable. This can be achieved by making thethird tubular structure 62 compressible in the desired direction ofdeflection and resilient to compression along a plane perpendicular tothe deflection. In this embodiment such variable compressibility isachieved with a centrally positioned spine 66 that is resilient tocompression along its axis yet is sufficiently flexible to bend in aplane perpendicular to its width. FIGS. 14B to 16L providerepresentative embodiments of the first embodiment with a second flexurezone 34 configured for controlled, multi-directional bending having acentral spine and multiple control wires.

In the embodiment of FIGS. 14A to 14C, the width of the spine 66 affectsthe relative stiffness and elasticity of the third tubular structure 62.It should be understood that the width of the spine 66 may be specifiedto provide the third tubular structure 62 with a desired relativestiffness and/or elasticity. Furthermore, the width of the spine 66 mayvary along the longitudinal axis of the third tubular structure 62,thereby providing the third tubular structure with a varying relativestiffness and/or elasticity along its length. Such variation in thewidth of the spine 66 may be gradual, continuous, abrupt, discontinuous,or combinations thereof.

A flat ribbon material (not shown) (e.g., Nitinol, stainless steel, orspring stainless steel) can be attached to the spine 66. When thepulling force is removed from the control wire 40, the flat ribbon,which serves to reinforce the deflectable third tubular structure 62,will elastically straighten out the deflectable third tubular structure62.

The length L3 of the second flexure zone 34 is between about 5 mm and 20mm, for example less than or equal to about 12.5 mm. As the distal endregion 20 is advanced from a guide catheter into a renal artery theenergy delivery element 24 contacts the superior surface of the renalartery wall. The length L3 allows the energy delivery element 24 to bemanipulated through deflection of the second flexure zone 34 to contactdorsal, ventral and inferior surfaces of the renal artery wall within ashort distance as long as a portion of the second flexure zone 34protrudes from the guide catheter. Thus the length L3 of the secondflexure zone 34 is chosen to be specially suited for use in a renalartery.

The width of the ribs 68 (i.e., the distance spanned by each rib alongthe longitudinal axis of the third tubular structure 62), as well as thespacing of the ribs 68 (i.e., the distance spanned by the spine 66 alongthe longitudinal axis of the third tubular member 62 between adjacentribs 68), optionally may affect a maximal preferential deflectionachievable by the intermediate flexure zone 34 before adjacent ribs 68contact one another, i.e. may limit the maximum amount of compression tothe side of the third tubular structure that is compressible. Suchcontact between adjacent ribs 68 optionally may define the radius ofcurvature and/or the angle α2 (see FIG. 8C) of the second flexure zone34 under such maximal preferential deflection. The second flexure zoneis configured for a state of maximum flexure, wherein the state ofmaximum flexure is achieved when the deflectable body moves the energydelivery element away from the axis of the elongated tubular shaft by apredetermined distance. The maximum flexure avoids the risk of causingtrauma to the renal artery wall which could happen if a second flexurezone 34 of length L3 were deflected significantly more than the diameterof a renal artery. As will be discussed in more detail later, the thirdflexure zone 44 is configured to dampen force exerted to the artery wallwhen the second flexure zone 34 is deflected. Stable contact forcebetween an energy delivery element 24 and an inner wall of a renalartery can be created by exerting a force that is greater than aninstable force and less than a traumatic force. The third flexure zone44 dampens the contact force keeping it within a stable yet atraumaticrange even when the second flexure zone 34 moves the energy deliveryelement 24 away from the axis of the elongated tubular shaft by adistance greater than the diameter of a renal artery. For example, thethird flexure zone 44 may flex enough for the second flexure zone 34 tobe configured for a state of maximum flexure such that the predetermineddistance is less than or equal to about 4 mm greater than a renal arterydiameter. In one embodiment the distal assembly 53 has a length of about3 mm to 6 mm (e.g. less than or equal to 5 mm), the second flexure zone34 has a length L3 of about 8 mm to 15 mm (e.g. less than or equal to12.5 mm) and has a maximum flexure displacing the energy deliveryelement 24 a predetermined distance of about 10 to 15 mm. Alternativelyor additionally, the predetermined distance can be adjusted by adeflection limiter in the handle 200 that limits the actuator 260 todisplacing the control wire a maximum amount thus limiting thedeflection to an adjusted state of maximum flexure.

It should be understood that the width and/or the spacing of the ribs 68may be specified as desired to achieve a desired maximal preferentialdeflection. Furthermore, the width and/or the spacing of the ribs 68 mayvary along the longitudinal axis of the third tubular structure 62,thereby providing the intermediate flexure zone 34 with a varying radiusof curvature under such maximal preferential deflection. Such variationin the width and/or spacing of the ribs 68 may be gradual, continuous,abrupt, discontinuous, or combinations thereof.

In the embodiment of FIGS. 14B and 14C, the second flexure zone isconfigured for controlled, bi-directional bending. As seen in thecross-section of FIG. 14B, the third tubular structure 62 of the secondflexure zone 34 comprises a centrally positioned spine 66 having asubstantially flat or ribbon shape (i.e., the spine's width issignificantly greater than its thickness) that substantially divides thethird tubular structure in half. A central lumen 61 may be formedthrough the center of the spine 66 for passage of electricaltransmission wire(s) and/or sensor/thermocouple wire(s) 29.Alternatively, wire(s) 29 can pass through a lumen defined by centrallypositioned spine 66 and ribs 68.

Third tubular structure 62 may be fabricated, for example, viaElectrical Discharge Machining (EDM), micromachining and/or extrusion,to form a tube with a ribbon having a lumen, wherein the ribbon bisectsthe tube, as in FIG. 14B. As seen in FIG. 14C, a laser-cut pattern thenmay remove sections of the ribboned tube along its length to formconnecting ribs 68 a and 68 b at spaced intervals along the tube'slength that extend on opposing sides of spine 66 about the circumferenceof the third tubular structure 62. Control wires 40 a and 40 b areattached to a distal end of the second flexure zone with solder 130 onopposing sides of spine 66 and travel along the length of the thirdtubular structure radially positioned between the spine 66 and the ribs68.

The geometry of spine 66, in combination with the geometry of ribs 68 aand 68 b and the distal attachment locations of control wires 40 a and40 b, facilitate controlled, bi-directional bending of the secondflexure zone 34, e.g., by substantially constraining buckling or bendingof the spine 66 in response to pulling of a wire 40 a or 40 b to planesperpendicular to the width of the spine. The second flexure zonedeflects in a first direction in response to pulling on the control wire40 a while the control wire 40 b is not under significant tension (seeFIG. 14C). The second flexure zone deflects in a second, opposingdirection in response to pulling on the control wire 40 b while thecontrol wire 40 a is not under significant tension.

While FIGS. 14B and 14C illustrate a bi-directional bending embodimentof the second flexure zone 34, the third tubular structure 62 may befabricated with a centrally positioned spine that facilitates bending inany number of directions, as desired. FIGS. 16A to 16G illustrate anembodiment of the second flexure zone with a centrally positioned spinethat is configured for controlled, quad-directional deflection. As seenin FIGS. 16D to 16F, the third tubular structure 62 comprises centrallypositioned spine 66 with longitudinally-spaced spinal ribbon sections 66a and 66 b whose widths are angularly offset from one another by about90° in an alternating pattern along the length of the third tubularstructure. A centrally-positioned lumen extends through the ribbonsections along the length of the third tubular structure for passage ofelectrical transmission wire(s) and/or sensor/thermocouple wire(s) 29.Between each pair of the spinal ribbon sections 66 a and 66 b, the spine66 flares radially outward to form a spinal ribbon connector section 66c that connects the pair of spinal ribbon sections.

In the embodiment of FIGS. 16D to 16F, each connector section 66 c hasfour sides or extensions that extend to the circumference of the thirdtubular structure 62. The four sides or extensions have radial-mostpoints that are angularly offset by about 45° from the widths of ribbonsections 66 a and 66 b. Connecting ribs 68 a, 68 b, 68 c and 68 dconnect each of the four sides or extensions of each connector section66 c at the radial-most points, forming a circumferential ring or hoopat the level of each connector section 66 c.

Third tubular structure 62 thus comprises a series of repeating segmentsalong the length of the structure. Each repeating segment has a firstconnector section 66 c with ribs 68; followed lengthwise by a ribbonsection 66 a having a width that is 45° angularly offset from theradial-most points of the sides or extensions of the first connectorsection 66 c; followed lengthwise by a second connector section 66 cwith ribs 68, the second connector section having sides or extensionswith radial-most points that are 45° angularly offset from the width ofthe ribbon section 66 a and that are angularly aligned with theradial-most points of the sides or extensions of the first connectorsection 66 c; followed lengthwise by a ribbon section 66 b having awidth that is 45° angularly offset from the radial-most points of thesides or extensions of the second connector section 66 c and that is 90°angularly offset from the width of ribbon section 66 a; followedlengthwise by a repeating first connector section 66 c with ribs 68, therepeating first connector section having sides or extensions withradial-most points that are 45° angularly offset from the width of theribbon section 66 b and that are angularly aligned with the radial-mostpoints of the sides or extensions of the second connector section 66 c;etc.

The ribbon sections 66 a and 66 b preferably have widths that are lessthan the diameter of third tubular structure 62 at the level of eachconnector section 66 c (e.g., less than the diameter of the rings formedby ribs 68), such that the geometry of the repeating segments of thethird tubular structure 62 forms four lengthwise voids along the lengthof the third tubular structure. Two of the voids are substantiallyaligned with, but positioned radially outward of, the width of thespinal ribbon section 66 a, while the remaining two voids aresubstantially aligned with, but positioned radially outward of, thewidth of the spinal ribbon section 66 b. Thus, the four voids are about45° angularly offset from the radial-most points of the sides orextensions of the connector sections 66 c, i.e. the voids occupy thespace between the sides or extensions where the sides or extensionsextend to the circumference of the third tubular structure 62 and areconnected by ribs 68.

A control wire 40 a, 40 b, 40 c or 40 d is positioned within each of thevoids along the length of the third tubular structure and is attached toa distal end of the second flexure zone with solder 130. Pulling on anyone of the control wires while the other three control wires are notunder significant tension may provide controlled deflection of thesecond flexure zone 34 in the direction of the wire being pulled(alternatively, any three control wires may be pulled while the fourthcontrol wire is not under significant tension in order to providecontrolled deflection of the second flexure zone in the oppositedirection of the control wire not being pulled). In this manner, thesecond flexure zone 34 may be configured for controlled,quad-directional bending in four directions that are about 90° angularlyoffset or out of phase from one another.

For example, as seen in FIG. 16E, pulling on wire 40 a causes ribbonsections 66 a, whose widths are in a plane perpendicular to the plane ofwire 40 a, to buckle or bend in the direction of the wire 40 a,providing controlled bending of the third tubular structure 62 andsecond flexure zone 34 in the direction of the wire 40 a. Likewise, asseen in FIG. 16F, pulling on wire 40 b causes the ribbon sections 66 bto buckle or bend in the direction of the wire 40 b, providingcontrolled bending of the second flexure zone 34 in the direction of thewire 40 b. Conversely, pulling on wire 40 c would cause the ribbonsections 66 a (and thereby the second flexure zone 34) to buckle or bendin the opposite direction of that achieved with wire 40 a (not shown),while pulling on wire 40 d would cause the ribbon sections 66 b (andthereby the second flexure zone 34) to buckle or bend in the oppositedirection of that achieved with wire 40 b (not shown).

In some multi-directional deflection embodiments, such as those shown inFIGS. 16D to 16G, pulling on any two adjacent control wires while theremaining control wires are not under significant tension may providecontrolled deflection of the second flexure zone 34 in additionaldirections offset or out of phase from the directions achieved bypulling on any single control wire 40. When two adjacent wires arepulled, substantially all of the alternating ribbon sections 66 a and 66b would be expected to buckle or bend. Ribbon sections 66 a would beexpected to bend in their flexibly biased plane in the direction ofapplied tension by a first control wire, while alternate ribbon sections66 b would be expected to bend in their flexibly biased plane in thedirection of applied tension by a second adjacent control wire. Thealternating ribbon sections would bend in directions which are about 90°offset from one another. The amount of bending the alternating ribbonsections 66 a and 66 b would be proportionate to the amount of tensionapplied by each respective control wire. The cumulative effect, alongthe total length of the second flexure zone 34, of bending bothalternating ribbon sections would be a bend in the direction between thetwo flexibly biased planes. In this manner, the second flexure zone 34may be configured for controlled deflection in four directions bypulling one of the four control wires 40, and additional directions bypulling two adjacent control wires 40 with equal or disproportionatetensions.

The third tubular structures 62 of FIGS. 16D to 16F may, for example, befabricated from a combination of EDM, micromachining and/or extrusion,as well laser cutting. As seen in FIG. 16A, the third tubular structuremay be fabricated via EDM, micromachining and/or extrusion with thecross section of spinal connector sections 66 c. As seen in FIG. 16C,laser cutting in a first side-sectional plane of the third tubularmember 62 that is about 45° angularly offset from points at which theinterior portion of the third tubular structure connects to the tubularouter portion, may form spinal ribbon sections 66 a, as well asdiametric narrowing at the level of spinal ribbon sections 66 b.Likewise, as seen in FIG. 16B, laser cutting in a second side-sectionalplane of the third tubular member 62 that is perpendicular to (i.e.,that is 90° angularly offset from) the first side-sectional plane mayform spinal ribbon sections 66 b and spinal connector sections 66 c, aswell as diametric narrowing at the level of the spinal ribbon sections66 a. This provides the spinal connector sections 66 c with four sides,as in FIG. 16D.

With reference now to FIG. 16G, an alternative configuration of thethird tubular structure configured for quad-directional controlleddeflection (and deflection in additional directions when two adjacentcontrol wires are pulled, as previously described) is described. In FIG.16G, each of the spinal ribbon sections 66 a and 66 b flares radiallyoutward to connect to the spinal connector sections 66 c along only twosides or extensions that extend to the circumference of the thirdtubular structure 62. The two sides or extensions have radial-mostpoints that are substantially aligned with the widths of each of theribbon sections 66 a and 66 b, respectively. Connecting ribs 68 a and 68b, 68 c and 68 d connect each of the four sides or extensions found ateach connector section 66 c (two such sides or extensions emanating fromeach of the ribbon sections 66 a and 66 b, respectively, about 90° outof phase with the other two sides or extensions), forming acircumferential ring or hoop at the level of each connector section 66c.

Third tubular structure 62 thus comprises a series of repeating segmentsalong the length of the structure. Each repeating segment has a firstconnector section 66 c with ribs 68; followed lengthwise by a ribbonsection 66 a having a width that is angularly aligned with two of theradial-most points of the sides or extensions of the first connectorsection 66 c and about 90° out of phase with the other two sides orextensions of the first connector section; followed lengthwise by asecond connector section 66 c with ribs 68, the second connector sectionhaving four sides or extensions with four radial-most points, two ofwhich are again aligned with the width of the ribbon section 66 a andtwo that are about 90° out of phase with the ribbon section 66 a;followed lengthwise by a ribbon section 66 b having a width that is 90°angularly offset from the two radial-most points of the sides orextensions of the second connector section 66 c that are aligned withthe width of ribbon section 66 a, and having a width that is angularlyaligned with the remaining two radial-most points of the secondconnector section 66 c; followed lengthwise by a repeating firstconnector section 66 c with ribs 68, the repeating first connectorsection having four sides or extensions with four radial-most points,two of which are again aligned with the width of the ribbon section 66 band two that are about 90° out of phase with the ribbon section 66 b;etc.

In the embodiment of FIG. 16G, two lumens extend through each ribbonsection 66 a and 66 b, respectively, near either end of the width ofeach ribbon section (i.e., four such lumens in all, in addition to thecentrally-positioned lumen for passage of wire 29). Control wires 40 maybe routed through these lumens for controlled quad-directionaldeflection (and deflection in additional directions when two adjacentcontrol wires are pulled) of the second flexure zone 34, as describedpreviously.

FIGS. 14B and 14C illustrate a second flexure zone 34 with a centrallypositioned spine 66 configured for bi-directional controlled deflection,while FIGS. 16D to 16F illustrate second flexure zones 34 with acentrally positioned spine 66 configured for quad-directional controlleddeflection (and deflection in additional directions when two adjacentcontrol wires are pulled, as previously described). The second flexurezone alternatively may comprise a centrally positioned spine 66configured for deflection in any number of additional directions, asdesired. For example, additional ribbon sections may be provided atadditional angular offsets and connected by spinal connector sectionshaving additional sides (e.g., as seen in FIG. 16H, for six-directionalbending, three alternating spinal ribbon sections may be provided at 60°angular offsets, connected by spinal connector sections having six sidesor extensions whose radial-most points extend to the circumference ofthe third tubular structure 62 in angular alignment with the edges ofthe spinal ribbon sections, such that six voids are created that areoffset by about 30° from the width of any spinal ribbon section). Whencombined with appropriate ribs 68 and control wires 40, controlleddeflection in any number of directions may be achieved. However, it isexpected that the second flexure zone 34 may become increasingly stiffas the number of alternating ribbon sections increases, which may placea practical limit on the attainable number of controlled deflectiondirections.

Referring now to FIGS. 16I and 16J, as an alternative to a secondflexure zone 34 with a third tubular structure 62 comprising a centrallypositioned spine in combination with a laser-cut pattern that formsconnecting ribs, the second flexure zone 34 may comprise a centrallypositioned spine 66 that is surrounded by a coiling third tubularstructure 62. A coiling third tubular structure may increase flexibilityof the second flexure zone 34. The coiling third tubular structure maycomprise a laser-cut hypo tube, a hollow coil, a hollow cable, a braidedshaft, etc. The spine may be connected to the coiling third tubularstructure 62 along its length, may be connected to the structure at onlyone or a few locations (e.g., at its distal end), or may float or befriction fit within the coiling third tubular structure.

The spine 66 may comprise any of the spines seen in FIG. 14B to 16H(e.g., may be flat or ribbon-like, as in FIGS. 14B and 14C; or maycomprise angularly offset, alternating ribbons, as in FIGS. 16D to 16H),or may comprise any additional number of alternating ribbons, asdesired, to facilitate controlled deflection in any number ofdirections, as desired. The spine may be fabricated, for example, viaEDM, micromachining and/or extrusion and may comprise a laser-cutpattern along its length that increases flexibility. The spine mayalternate along its length, e.g., in a spiraling laser-cut pattern.

In FIGS. 16I and 16J, second flexure zone 34 illustratively isconfigured for controlled, bi-directional deflection. The spine 66comprises a flat or ribbon-shaped spine, and the coiling third tubularstructure 62 surrounds the spine. Control wires 40 a and 40 b areattached to a distal end of the second flexure zone with solder 130 onopposing sides of the spine 66. As in the embodiment of FIGS. 14B and14C, pulling on the control wire 40 a while the control wire 40 b is notunder significant tension (see FIG. 16J) deflects the second flexurezone 34 in a first direction. The second flexure zone deflects in asecond, opposing direction in response to pulling on the control wire 40b while the control wire 40 a is not under significant tension.

4. Third Flexure Zone

As shown in FIGS. 18A to 18H, the third or distal flexure zone 44comprises a flexible structure 74. The flexible structure 74 cancomprise a metal, a polymer, or a metal/polymer composite. The materialand physical features of the flexible structure 74 could optionally beselected so that the axial stiffness and torsional stiffness of theflexible structure 74 is not greater than the axial stiffness andtorsional stiffness of the third tubular structure 62. The overallflexibility of the flexible structure 74 could optionally be at leastequal to and desirably greater than the flexibility of third tubularstructure 62 when the third tubular structure has not been deflected bythe control wire 40.

The material and physical features of the flexible structure 74 areselected so that the distal flexure zone 44 has (1) sufficientflexibility to elastically deform when an thermal heating element 24applies a pressure to an inner wall of a renal artery that is less thana pressure that is at high risk of causing trauma; but (2) sufficientstiffness to create contact force or pressure between the thermalheating element 24 and inner wall of the renal artery that allows forenergy delivery and stable contact. The flexibility of the distalflexure zone 44 dampens the force applied by the thermal heating element24 to the artery wall so that the force remains in this suitable rangeas the second flexure zone 34 is deflected over a wide useable range.Furthermore, by elastically deforming, a third flexure zone 44 aligns athermal heating element 24 so that its side is in contact with theartery wall as previously discussed.

The flexible structure 74, as a part of the third flexure zone 44, canbe coupled to the second flexure zone as described above. As shown inFIG. 18B, the thermal heating element 24 is carried at the distal end ofthe flexible structure 74 for placement in contact with tissue along avessel wall of a respective renal artery.

The material selected for the flexible structure 74 can be radiopaque ornon-radiopaque. For example, a radiopaque material, e.g., stainlesssteel, platinum, platinum iridium, or gold, can be used to enablevisualization and image guidance. When using a non-radiopaque material,the material optionally may be doped with a radiopaque substance, suchas barium sulfate, to facilitate visualization and image guidance.

The configuration of the flexible structure 74 can vary. For example, inthe embodiment depicted in FIGS. 18B and 18C, the flexible structure 74comprises a thread 104 encased in, or covered with, a polymer coating orwrapping 110. The thread 104 is routed through a proximal anchor 108,which is attached to the distal end of the second flexure zone 34, and adistal anchor 106, which is fixed within or integrated into the heatingelement 24/electrode 46. The distal anchor 106 may be fixed within theheating element 24/electrode 46 using, e.g., solder. Alternatively, thedistal anchor 106 and heating element 24/electrode 46 may fabricated asa single piece or unitary structure.

Although various types of materials can be used to construct theaforementioned structures, in order to have a flexible structure 74 thatsecurely connects to the second flexure zone 34 and the thermal heatingelement 24, it is desirable for thread 104 to be comprised of Kevlar orsimilar polymer thread and for the proximal anchor 108 and distal anchor106 to be comprised of stainless steel. While the coating 110 can becomprised of any electrically insulative material, and particularlythose listed later with respect to sheath 80, it is desirable for thestructures of the flexible structure 74 to be encased/coated/covered bya low-durometer polymer such as carbothane laminate 110. As shown inFIG. 18C, one or more supply wires 29 may run alongside or within theflexible structure 74. As previously mentioned these wires may providethe thermal heating element 24 with electrical current/energy from thegenerator 26 and also convey data signals acquired by sensor 52. Asdepicted in FIG. 18C, the control wire 40 extending from the handleactuator 260 can be formed into the proximal anchor 108 and attached tothe elongated shaft using solder 130.

One advantage of the above-described configuration of the flexiblestructure 74 is that the flexible structure 74 creates a region ofelectrical isolation between the thermal heating element and the rest ofthe elongated shaft. Both the Kevlar thread 104 and laminate 110 areelectrically insulative, thereby providing the supply wire(s) 29 as thesole means for electrical connectivity. Accordingly, the externalsurface of the flexible structure 74 and third flexure zone 44 iselectrically inactive.

As shown in FIGS. 18D through 18F, the flexible structure 74 allowsconsiderable passive deflection of the third flexure zone 44 when thethermal heating element 24 is put into contact with the vessel wall. Asalready described, this flexibility has several potential benefits. Onesuch benefit may be the ability of the third flexure zone 44 to reduceforce or stress applied between the thermal heating element 24 and thevessel wall when or as the second flexure zone 34 is deflected, relativeto the force or stress that would be applied to the vessel wall duringsecond flexure zone 34 deflection if the third flexure zone 44 were tobe removed and the thermal heating element were to be coupled directlyto the distal end of the second flexure zone 34. This may reduce a riskof trauma. Furthermore, the force or stress applied by the thermalheating element 24 to the vessel wall may be maintained in a consistentrange during second flexure zone 34 deflection, particularly duringmovement caused by respiration and/or pulsatile flow, which mayfacilitate consistent and/or controlled lesion creation.

The size and configuration of the flexible structure 74 enables thethermal heating element to deflect in many directions because the thirdflexure zone may bend by angle Θ in any plane through the axis of thedistal end region. For treatments within a peripheral blood vessel suchas the renal artery, it is desirable that angle Θ≦90 degrees.Optionally, the flexible structure 74 is not very resilient, i.e., doesnot provide a significant restoring or straightening moment whendeflected.

The thermal heating element 24 desirably may provide omni-directionaldelivery of energy in substantially any or all directions. As the thirdflexure zone 44 passively deflects at a treatment site about an angle Θappropriate to a given patient's anatomical geometry, any portion of thethermal heating element 24 may be aligned with an interior wall of therenal artery for energy delivery to target renal nerves. Blood flow mayremove heat during such energy delivery, thereby reducing or mitigatinga need for shielding or other preferential directing of the energydelivered to the target renal nerves that could make the third flexurezone 44 undesirably stiffer or bulkier. Such omni-directional energydelivery without shielding/preferential directing may facilitate simpleror safer positioning of the thermal heating element 24 at a treatmentsite, as compared to shielded or directed thermal heating elements, e.g.thermal heating elements comprising a microwave or radioactive powersource.

In alternative embodiments of the third flexure zone 44, the flexiblestructure 74 can take the form of a tubular metal coil, cable, braid,polymer or metal/polymer composite, as FIG. 18H shows. Alternatively,the flexible structure 74 can take the form of an oval, or rectangular,or flattened metal coil or polymer, as FIG. 18G shows. In alternateembodiments, the flexible structure 74 may comprise other mechanicalstructures or systems that allow the thermal heating element 24 to pivotin at least one plane of movement. For example, the flexible structure74 may comprise a hinge or ball/socket combination.

If the flexible member comprises, in whole or in part, an electricallyconductive material, the third flexure zone 44 desirably includes anouter sheath 80 (see FIGS. 18G and 18H) or covering over the flexiblestructure 74 made from an electrically insulating polymer material. Thepolymer material also possesses a desired durometer for flexibility ofthe flexible member (e.g., 25D to 55D).

Candidate materials for the polymer material include polyethyleneterephthalate (PET); Pebax; polyurethane; urethane, carbothane,tecothane, low density polyethylene (LDPE); silicone; or combinationsthereof. The polymer material can be laminated, dip-coated,spray-coated, or otherwise deposited/applied over the flexible structure74. Alternatively, a thin film of the polymer material (e.g., PTFE) canbe wrapped about the flexible structure 74. Alternatively, the flexiblestructure 74 can be inherently insulated, and not require a separatesheath 80 or covering. For example, the flexible structure can comprisea polymer-coated coiled wire.

Optionally, third flexure zone 44 can include a sensor 42 that indicatesan amount of deflection of third flexure zone 44 as shown in FIG. 19A.The sensor 42 can be, for example, a piezo-resistive element that is afull or partial length of the third flexure zone 44 and can be mountedto a side of the third flexure zone. A pair of conductors (not shown)running through the elongated shaft 16 would connect the sensor 42 to anelectrical supply and sensing circuit (not shown). When the thirdflexure zone 44 is deflected in response to a force applied to thethermal heating element 24 or a portion of the third flexure zone 44 byan inner wall of a renal artery, the sensor 42 will deliver a signalthat quantifies the amount of deflection. When the sensor 42 is apiezo-resistive element its resistance will change proportional to itsstrain. The amount of deflection of third flexure zone 44 is anindication of contact force with the inner wall of the renal artery.

5. Handle Actuator for Controlled, Multi-Directional Deflection

In one representative embodiment, as shown in FIG. 17A, the actuator 260of handle assembly 200 comprises a ball-and socket joint for controlledmulti-directional deflection of the second flexure zone 34 viacontrolled pulling on one or more control wires 40 that proximallyterminate at the actuator and distally terminate in the second flexurezone. FIG. 17A illustratively shows four control wires 40circumferentially spaced about the handle assembly 200 and that extendcircumferentially to the second flexure zone. The actuator 260 canswivel in all directions relative to the handle assembly, allowing anywire (or wires) to be pulled in tension, as desired, to deflect thesecond flexure zone 34 in multiple directions in a controlled manner.

An alternative multi-directional actuator 260 may comprise amultidirectional joystick coupled to multiple control wires, as in FIG.17B. Alternatively, one or more bi-directional actuators, each foractuation in two directions in a given plane, may be provided.

B. Second Representative Embodiment (First Flexure Zone, Second FlexureZone with a Circumferentially Positioned Spine, and Third Flexure Zonewith Distally Carried Thermal Heating Element)

FIGS. 21A to 21F show representative embodiments of the secondembodiment with an elongated shaft 16 that includes a proximal forcetransmitting section 30, a first or proximal flexure zone 32, a secondor intermediate flexure zone 34, and an optional third or distal flexurezone 44. In these embodiments, the materials, size, and configuration ofthe proximal force transmitting section 30, first flexure zone 32, andoptional third flexure zone 44 are comparable to their respectivecounterparts described in any of the previous embodiments.

In these embodiments, however, the second flexure zone 34 may comprise athird tubular structure 62 with two or more circumferentially positionedspines 66. As discussed in greater detail above, preferential deflectionof the second flexure zone in multiple directions is desirable. This canbe achieved by making the third tubular structure 62 compressible in thedesired direction of deflection and resilient to compression along aplane perpendicular to the deflection. In this embodiment such variablecompressibility is achieved with two or more circumferentiallypositioned spines that are resilient to compression yet are sufficientlyflexible to bend in a direction of biased compressibility. Twocircumferentially positioned spines that are resilient to compressionform a plane that is resilient to compression and that passes throughthe two circumferentially positioned spines. FIGS. 21A to 21F illustraterepresentative embodiments of the second embodiment with a secondflexure zone 34 having multiple circumferentially positioned spines andcontrol wires 40 configured for controlled, multi-directional bending.

In the embodiment of FIGS. 21A and 21B, the second flexure zone 34 isconfigured for controlled, bi-directional bending. As seen in thecross-section of FIG. 21A, the third tubular structure 62 of the secondflexure zone 34 comprises a laser-cut pattern that forms angularlyopposed (i.e., about 180° angularly offset), circumferentiallypositioned spines 66 a and 66 b that divide the circumference of thethird tubular structure into two halves that are connected by connectingribs 68 a and 68 b, respectively, positioned on either side of the thirdtubular structure about its circumference. The connecting ribs 68 a and68 b may each span an arcuate segment of about 180° about thecircumference of the third tubular structure. Control wires 40 a and 40b are attached to a distal end of the second flexure zone with solder130 a and 130 b, respectively on opposing sides of third tubularstructure 62, angularly offset from spines 66 a and 66 b.

The width of each spine 66 a and 66 b is not significantly greater thanthe depth of each spine, respectively (e.g., the width of each spine maybe less than, or equal to, its depth), in order to facilitatebi-directional deflection of the third tubular structure 62 in thedirections of the ribs 68 a and 68 b, while restricting deflection inthe directions of the spines (i.e., restricting deflection in the planeincluding the two spines). Optionally, ribs 68 a on a first side of thethird tubular structure 62 may alternate with ribs 68 b on the oppositeside of the third tubular structure along the length of the structure,which may increase flexibility and/or facilitate controlled deflectionof the second flexure zone 34.

The geometry of spines 66 a and 66 b, as well as of ribs 68 a and 68 b,in combination with the distal, angularly offset attachment locations ofcontrol wires 40 a and 40 b, facilitate controlled, bi-directionalbending of the second flexure zone 34. The second flexure zone deflectsin a first direction in response to pulling on the control wire 40 awhile the control wire 40 b is not under significant tension (see FIG.21B). The second flexure zone deflects in a second, opposing directionin response to pulling on the control wire 40 b while the control wire40 a is not under significant tension.

While FIGS. 21A and 21B illustrate a bi-directional bending embodimentof the second flexure zone 34, the third tubular structure 62 may befabricated to facilitate bending in any number of directions, asdesired, by adding additional circumferentially positioned spinesconnected by ribs, and by adding additional control wires. For example,FIGS. 21C and 21D illustrate an embodiment of the second flexure zoneconfigured for controlled, tri-directional deflection. In FIGS. 21C and21D, the third tubular structure 62 of the second flexure zone 34comprises a laser-cut pattern that forms angularly offset,circumferentially positioned spines 66 a, 66 b and 66 c that divide thecircumference of the third tubular structure into thirds that areconnected by connecting ribs 68 a, 68 b and 68 c, respectively,positioned about the circumference of the third tubular structure. Thespines may be angularly offset by about 120° from one another about thecircumference of the third tubular structure.

The spines comprise longitudinally spaced expansion elements 67, such asundulating or S-shaped elements, which resist compression of the spinesduring compressive bending while facilitating moderate elongation of thespines during tensile bending. When a spine 66 is bent in a manner thatelongates the spine (e.g., places the spine in tension), the expansionelements 67 at least partially straighten to accommodate such spinalelongation. Conversely, when a spine 66 is bent in a manner thatshortens the spine (e.g., places the spine in compression), theexpansion elements 67 have a geometry that resists such spinalcompression. In this manner, the expansion elements 67 allow spines 66to accommodate controlled deflection in desired directions, whileresisting deflection in other directions. Optionally, expansion elements67 (as well as the spines 66 or the third tubular structure 62) may befabricated from a shape memory alloy, such as Nitinol, so that theexpansion elements resume their undulating shape after removal oftension from a spine 66.

In each one third arc segment of the circumference of the third tubularstructure 62 positioned between the spines, a control wire 40 a, 40 b or40 c is attached to a distal end of the second flexure zone with solder130. The control wires 40 a, 40 b, and 40 c can held in positionrelative to the spines 66 a, 66 b, and 66 c by a spacing element (notshown) which could be, for example, a flexible extruded polymer tubecomprising lumens for the control wires. Pulling on any one of thecontrol wires while the other two control wires are not undersignificant tension may provide controlled deflection of the secondflexure zone 34 in the direction of the wire being pulled. For example,when control wire 40 c is pulled the two adjacent spines 66 c and 66 bresist compression and provide a bending moment. The third tubularstructure 62 compresses on the side of the bending moment where thecontrol wire 40 c is being pulled, and expands on the opposing side ofthe bending moment. The expansion elements 67 of the spine 66 a that ispositioned substantially in angular opposition to the control wire 40 cbeing pulled, at least partially expand (at least temporarily) toaccommodate the bending of third tubular structure. In this manner, thesecond flexure zone 34 may be configured for controlled, tri-directionalbending in three directions that are about 120° offset or out of phasefrom one another.

FIGS. 21E and 21F illustrate an embodiment of the second flexure zoneconfigured for controlled, quad-directional deflection. In FIGS. 21E and21F, the third tubular structure 62 of the second flexure zone 34comprises a laser-cut pattern that forms angularly offset,circumferentially positioned spines 66 a, 66 b, 66 c and 66 d havingexpansions elements 67 and that divide the circumference of the thirdtubular structure into quartiles that are connected by connecting ribs68 a, 68 b, 68 c and 68 d, respectively, positioned about thecircumference of the third tubular structure. The spines may beangularly offset by about 90° about the circumference of the thirdtubular structure.

In each quartile arc segment of the circumference of the third tubularstructure 62 positioned between the spines, a control wire 40 a, 40 b,40 c or 40 d is attached to a distal end of the second flexure zone withsolder 130. Pulling on any one of the control wires while the otherthree control wires are not under significant tension may providecontrolled deflection of the second flexure zone 34 in the direction ofthe wire being pulled. In this manner, the second flexure zone 34 may beconfigured for controlled, quad-directional bending in four directionsthat are about 90° offset or out of phase from one another.

FIGS. 21A-21F illustrate a second flexure zone 34 with circumferentiallypositioned spines configured for bi-, tri-, or quad-directionalcontrolled deflection. As will be apparent to those of skill in the art,the laser-cut pattern of third tubular structure 62 may comprise anynumber of circumferentially positioned spines 66 having expansionelements 67 and connected by connecting ribs 68 about the structure'scircumference to divide the circumference into any number of arcsegments (e.g., halves, thirds, quartiles, quintiles, sextiles,septiles, octiles, nontiles, deciles, etc.), as desired. When combinedwith appropriate control wires, controlled deflection in any number ofdirections may be achieved. However, it is expected that the secondflexure zone 34 will become increasingly stiff as the number of arcsegments about its circumference (i.e., as the number ofcircumferentially positioned spines) increases, which may place apractical limit on the attainable number of controlled deflectiondirections.

C. Third Representative Embodiment (Second Flexure Zone Includes aPre-Formed Shape)

FIGS. 22A-22F show representative embodiments of the third embodimentwith an elongated shaft 16 that includes a proximal force transmittingsection 30, a first or proximal flexure zone 32, a second orintermediate flexure zone 34, and an optional third or distal flexurezone 44. In these embodiments, the materials, size, and configuration ofthe proximal force transmitting section 30, first flexure zone 32, andoptional third flexure zone 44 are comparable to their respectivecounterparts described in any of the previous embodiments.

In these embodiments, however, the second flexure zone 34 may comprise athird tubular structure 62 with a pre-formed shape that, in anunrestrained configuration, is off-axis or deflected from thelongitudinal axis of the elongated shaft 16 (see, e.g., FIGS. 22A and22B), which may facilitate locating of the thermal heating element 24into contact with a treatment site within a renal artery. The length anddiameter of second flexure zone 34 may be comparable to those describedin any of the previous embodiments of the second flexure zone 34.Furthermore, the pre-formed shape of the third tubular structure 62 maybe specified to provide the second flexure zone 34 with a desired radiusof curvature RoC₂ and angle α2 (see FIG. 8C), such as those describedpreviously. The third tubular structure 62 may be fabricated, forexample, from a shape memory material, such as a nickel-titanium alloy(i.e., Nitinol) or from spring steel, to provide the pre-formed shape.

When advanced within, and retrieved from, a renal artery via anintravascular path, the second flexure zone 34 may be positioned withina guide catheter, such as guide catheter 96, which may substantiallystraighten or constrain the third tubular structure 62 during suchintravascular delivery and retrieval. After advancement of the secondflexure zone 34 distal of the guide catheter, the third tubularstructure 62 may re-assume its off-axis, pre-formed shape, e.g., tobring the thermal heating element 24 into contact with a wall of therenal artery. The second flexure zone 34 optionally may be activelydeflected (e.g., as described previously via wire 40 attached to handleactuator 260), in addition to the passive deflection provided by thepre-formed shape of the third tubular structure 62.

When the second flexure zone 34 is configured for both active andpassive deflection, the third tubular structure 62 may be configuredsuch that active deflection of the second flexure zone is biased in anopposite direction of the third tubular structure's pre-formed shape.This can be achieved by making the third tubular structure 62compressible in the opposite direction of the structure's pre-formedshape and resilient to compression in the direction of the structure'spre-formed shape. In such a configuration, active deflection reduces orreverses the passive deflection provided by the third tubularstructure's pre-formed shape.

FIG. 22C provides a representative embodiment of a second flexure zone34 that has a pre-formed shape and that is configured for activedeflection in the opposite direction of the pre-formed shape. In FIG.22C, the third tubular structure 62 again comprises a laser-cut patternthat includes spine 66 with connecting ribs 68. The spine 66 comprises apre-formed shape that positions the second flexure zone 34 off-axis ordeflected from the longitudinal axis of the elongated shaft 16 in anunrestrained configuration. The direction of the pre-formed shape issuch that the laser-cut pattern biases active deflection of the thirdtubular structure 62, in response to pulling on the control wire 40coupled to the distal end of the third tubular structure 62, away fromthe direction of the pre-formed shape.

As seen in FIGS. 22D-22F, when the second flexure zone 34 has apre-formed shape and is configured for active deflection in the oppositedirection of the pre-formed shape, the second flexure zone desirably mayachieve bi-directional bending via a single control wire 40. As seen inFIG. 22D, in the unrestrained configuration of the second flexure zone34 without active deflection (e.g., when the control wire 40 is notbeing pulled in tension), the second flexure zone 34 assumes thepre-formed shape of its third tubular structure 62. As seen in FIG. 22E,tension applied to control wire 40 partially or completely straightensthe bend in the second flexure zone 34. As seen in FIG. 22F, in someembodiments additional proximal tension (i.e. via pulling/proximalretraction) of control wire 40 may deflect the second flexure zone inthe opposite direction of its pre-formed shape, thereby providingbi-directional bending of the second flexure zone with a single controlwire 40.

Optionally, the control wire 40 may be under partial tension, as in FIG.22E, during delivery and/or retrieval of the thermal element 24 within arenal artery, in order to at least partially straighten the pre-formedshape of the second flexure zone 34 during such delivery/retrieval. Whenpositioned within the renal artery, tension may be removed from thecontrol wire 40 to deflect the second flexure zone in the direction ofits pre-formed shape, as in FIG. 22D, in order to bring the thermalelement 24 into contact with a wall of the renal artery. Additionally oralternatively, the control wire 40 may be pulled more proximally todeflect the second flexure zone in the opposite direction of itspre-formed shape, as in FIG. 22F, in order to bring the thermal element24 into contact with an opposing wall of the renal artery withoutnecessitating rotation of the elongated shaft 16. As discussedpreviously, the third flexure zone 44 desirably accommodates contactwith any wall of the renal artery and passively deflects to bring thethermal element 24 into at least partial alignment with the contactedwall of the artery, thereby accommodating bi-directional deflection ofthe second flexure zone 34.

D. Fourth Representative Embodiment (Second Flexure Zone Configured forDeflection at a Joint)

FIGS. 23A-23E show representative embodiments of the fourth embodimenthaving an elongated shaft 16 that includes a proximal force transmittingsection 30, a first or proximal flexure zone 32, a joint 35, and anoptional third or distal flexure zone 44 (see FIG. 23A). In theseembodiments, the materials, size, and configuration of the proximalforce transmitting section 30, first flexure zone 32, and optional thirdflexure zone 44 are comparable to their respective counterpartsdescribed in any of the previous embodiments.

However, in the fourth embodiment of the present invention, the secondflexure zone 34 is replaced by one or more joints 35 to facilitatedeflection of the third flexure zone 44. Joints 35 may provide precisedeflection control, as the joints may exhibit consistent deflectiondynamics. Furthermore, joints may provide a sharper bend than would beachievable with some of the previously described embodiments of thesecond flexure zone since joint bends have a Radius of Curvature RoC ofabout zero. Thus, the length of a jointed second flexure zone may beless than the length of a previously described biased spine secondflexure zone. This may facilitate thermal neuromodulation in shorterrenal arteries, and/or may facilitate use of a longer third flexure zone44 as shown in FIG. 23E. A longer third flexure zone may dissipatevessel contact force over its longer length and resiliently applypressure to the vessel wall to provide stable electrode contact duringpulsatile blood flow and respiratory motion. Also, a longer thirdflexure zone may be easier to visualize with fluoroscopy. The thirdflexure zone 44 may be between about 6 mm and 16 mm long, for exampleabout less than or equal to 9.5 mm, which could be suitable to providesufficient flexure in renal arteries.

With reference to FIG. 23B, in one representative embodiment of thefourth embodiment, hinge joint 35 that connects the proximal flexurezone 32 to the distal flexure zone 44. Control wires 40 a and 40 b areattached to either side of the joint 35, for example distal to the Axisof Rotation R, for rotating the distal flexure zone 44 about the Axis ofRotation R of the hinge joint. Alternatively, one control wire isattached to a side of a joint 35, for example distal to the Axis ofRotation R, for rotating the third flexure zone 44 about the Axis ofRotation R of the hinge joint and a spring rotates the third flexurezone 44 back to its unactuated state when tension in the control wire isrelieved. The unactuated state can be deflected in a second direction,providing multiple direction deflection with one control wire and aspring. A handle assembly 200 with an actuator 260 configured foractuating multiple wires may be provided (see, for example, FIG. 17A).

Alternatively, multiple distal flexure zones can be connected to theproximal flexure zone via one or more joints. Each distal flexure zonecan be attached to or comprise an electrode. Each distal flexure zonecan be actuated to rotate about the joint independently or together witha single control wire. Alternatively, a spring can be positioned in thejoint to push the distal flexure zones open and they can be closed bybeing retracted into a delivery sheath. When the distal flexure zonesare open the electrodes are moved away from one another and placed incontact with a vessel wall.

With reference to FIG. 23C, in one representative embodiment of thefourth embodiment, the second flexure zone 34 comprises first hingejoint 35 and second hinge joint 35′. Control wires 40 a and 40 b areattached to either side of the joint 35 for rotating the distal flexurezone about the Axis of Rotation R of the hinge joint 35, while controlwires 40 c and 40 d are attached to either side of the second joint 35′for rotating the third flexure zone about the Axis of Rotation R′ of thehinge joint 35′. The Axis of Rotation R′ of hinge joint 35′ preferablyis orthogonal to the Axis of Rotation R of hinge joint 35 to providedeflection of the distal flexure zone 44 in two orthogonal planes.

With reference to FIG. 23D, in one representative embodiment of thefourth embodiment, the second flexure zone 34 comprises ball-and-socketjoint 35 that joins proximal and distal flexure zones and thatfacilitates rotation in any plane with a Radius of Curvature RoC ofabout zero. Any number of control wires 40 (illustratively four controlwires) may be provided for deflecting the second flexure zone 34.

An alternative representation of the fourth embodiment (shown in FIG.23F) comprises multiple distal flexure zones 44 a and 44 b, eachattached to or comprising an electrode 24 a and 24 b respectively. Themultiple distal flexure zones are connected to the first flexure zonewith a joint 35. The distal flexure zones can be held in a closedposition with a spring placed in the joint. In a closed position themultiple e

IV. USE OF THE SYSTEM

A. Intravascular Delivery, Deflection and Placement of the TreatmentDevice

Any one of the embodiments of the treatment devices 12 described hereincan be delivered over a guide wire using conventional over-the-wiretechniques. When delivered in this manner (not shown), the elongatedshaft 16 includes a passage or lumen accommodating passage of a guidewire.

Alternatively, any one of the treatment devices 12 described herein canbe deployed using a conventional guide catheter or pre-curved renalguide catheter 94.

When using a guide catheter 94 (see FIG. 6A), the femoral artery isexposed and cannulated at the base of the femoral triangle, usingconventional techniques. In one exemplary approach, a guide wire (notshown) is inserted through the access site and passed using imageguidance through the femoral artery, into the iliac artery and aorta,and into either the left or right renal artery. A guide catheter can bepassed over the guide wire into the accessed renal artery. The guidewire is then removed. Alternatively, a renal guide catheter (shown inFIG. 24A), which is specifically shaped and configured to access a renalartery, can be used to avoid using a guide wire. Still alternatively,the treatment device can be routed from the femoral artery to the renalartery using angiographic guidance and without the need of a guidecatheter.

When a guide catheter is used, at least three delivery approaches can beimplemented. In one exemplary approach, one or more of theaforementioned delivery techniques can be used to position a guidecatheter within the renal artery just distal to the entrance of therenal artery. The treatment device is then routed via the guide catheterinto the renal artery. Once the treatment device is properly positionedwithin the renal artery, the guide catheter is retracted from the renalartery into the abdominal aorta. In this approach, the guide cathetershould be sized and configured to accommodate passage of the treatmentdevice. For example, a 6 French guide catheter can be used.

In a second exemplary approach, a first guide catheter is placed at theentrance of the renal artery (with or without a guide wire). A secondguide catheter is passed via the first guide catheter (with or withoutthe assistance of a guide wire) into the renal artery. The treatmentdevice is then routed via the second guide catheter into the renalartery. Once the treatment device is properly positioned within therenal artery the second guide catheter is retracted, leaving the firstguide catheter at the entrance to the renal artery. In this approach thefirst and second guide catheters should be sized and configured toaccommodate passage of the second guide catheter within the first guidecatheter (i.e., the inner diameter of the first guide catheter should begreater than the outer diameter of the second guide catheter). Forexample, the first guide catheter could be 8 French in size and thesecond guide catheter could be 5 French in size.

In a third exemplary approach, and as shown in FIG. 24A, a renal guidecatheter 94 is positioned within the abdominal aorta, just proximal tothe entrance of the renal artery. As now shown in FIG. 24B, thetreatment device 12 as described herein is passed through the guidecatheter 94 and into the accessed renal artery. The elongated shaftmakes atraumatic passage through the guide catheter 94, in response toforces applied to the force transmitting section 30 through the handleassembly 200. The first or proximal flexure zone 32 accommodatessignificant flexure at the junction of the left/right renal arteries andaorta to gain entry into the respective left or right renal arterythrough the guide catheter 94 (as FIG. 24B shows).

As FIG. 24C shows, the second or intermediate flexure zone 34 on thedistal end portion of the elongated shaft 16 can now be axiallytranslated into the respective renal artery, remotely deflected(illustratively, planar deflection or bending, but alternatively anyother previously described deflection, such as helical deflection, maybe provided) and/or rotated in a controlled fashion within therespective renal artery to attain proximity to and a desired alignmentwith an interior wall of the respective renal artery. As FIG. 24Cfurther shows, the optional third or distal flexure zone 44 bends toplace the thermal heating element 24 into contact with tissue on theinterior wall (alternatively or additionally, one or more thermalelements 24 may positioned along the length of the second flexure zone34 and brought into contact with tissue on the interior wall duringremote deflection of the second flexure zone).

As FIG. 24D shows a representative embodiment of a complex, multi-bendstructure formed by the first, second and third flexure zones 32, 24,and 44 of the distal end region 20 of the elongated shaft 16. Themulti-bend structure creates a consistent and reliable active surfacearea of contact between the thermal heating element(s) 24 and tissuewithin the respective renal artery (refer back to FIG. 9C). Thermalenergy can now be applied through the thermal heating element 24 toinduce one or more thermal heating effects on localized regions oftissue along the respective renal artery.

If upon deflection of second flexure zone 34 the thermal heating element24 does not make sufficient contact with tissue on the interior wall ofthe artery, as indicated for example by radiographic visualization or bya measurement of a sensor such as an impedance sensor, the distalassemble can be further manipulated until sufficient contact can bemade. Further manipulation can be accomplished by translation, rotation,deflection of the second flexure zone 34 in another direction, changingthe amount of deflection of the second flexure zone 34, or a combinationof the above. For example, if deflection of the second flexure zone 34in one direction, as shown in FIG. 24C does not result in sufficientcontact, second flexure zone 34 can be deflected in another direction asseen in FIG. 25A. Multiple-direction deflection provides more options tothe operator of the treatment device to obtain contact between thethermal element 24 and renal artery wall.

B. Creation of Thermally Affected Tissue Regions

As previously described (and as FIG. 24B shows), the thermal heatingelement 24 can be positioned by bending along the first flexure zone 32at a first desired axial location within the respective renal artery. AsFIG. 24C shows, the thermal heating element 24 can be radiallypositioned by deflection of second flexure zone 34 toward the vesselwall. As FIG. 24C also shows, the thermal heating element 24 can beplaced into a condition of optimal surface area contact with the vesselwall by further deflection of the third flexure zone 44.

Once the thermal heating element 24 is positioned in the desiredlocation by a combination of deflection of the second flexure zone 34,deflection of the third flexure zone 44 and/or rotation of the catheter,treatment can be administered. Optionally, infusate, such as saline, maybe delivered (e.g., may be infused through the thermal heating element,as in FIG. 11A) in the vicinity of the treatment site before, duringand/or after treatment to provide conductive and/or convective coolingin excess of that provided by blood flow. By applying energy through thethermal heating element 24, a first thermally affected tissue region98(a) can be formed, as FIG. 24D shows. In the illustrated embodiment,the thermally affected region 98(a) takes the form of a lesion on thevessel wall of the respective renal artery.

After forming the first thermally affected tissue region 98(a), thecatheter optionally may be repositioned for another thermal treatment.As described above in greater detail, it is desirable to create multiplefocal lesions that are circumferentially spaced along the longitudinalaxis of the renal artery. To achieve this result, the catheteroptionally may be retracted and, optionally, rotated to position thethermal heating element proximally along the longitudinal axis of theblood vessel. Rotation of the elongated shaft 16 from outside the accesssite (see FIG. 24E) may circumferentially reposition the thermal heatingelement 24 about the renal artery. Once the thermal heating element 24is positioned at a second axial and circumferential location within therenal artery spaced from the first-described axial position, as shown inFIG. 24E (e.g., 98(b)), another focal treatment can be administeredtreatment (with or without saline infusion). By repeating themanipulative steps just described (as shown in FIGS. 24F through 24K),the caregiver can create several thermally affected tissue regions98(a), 98(b), 98(c) and 98(d) on the vessel wall that are axially andcircumferentially spaced apart, with the first thermally affected tissueregion 98(a) being the most distal and the subsequent thermally affectedtissue regions being more proximal. FIG. 24I provides a cross-sectionalview of the lesions formed in several layers of the treated renalartery. This figure shows that several circumferentially and axiallyspaced-apart treatments (e.g., 98(a)-98(d)) can provide substantialcircumferential coverage and, accordingly, cause a neuromodulatoryeffect to the renal plexus. Clinical investigation indicates that eachlesion will cover approximately 30 percent of the circumferential areasurrounding the renal artery. In other embodiments, the circumferentialcoverage of each lesion can be as much as 60 percent.

In an alternative treatment approach, the treatment device can beadministered to create a complex pattern/array of thermally affectedtissue regions along the vessel wall of the renal artery. As FIG. 24Lshows, this alternative treatment approach provides for multiplecircumferential treatments at each axial site (e.g., 98, 99 and 101)along the renal artery. Increasing the density of thermally affectedtissue regions along the vessel wall of the renal artery using thisapproach might increase the probability of thermally-blocking the neuralfibers within the renal plexus.

The rotation of the thermal heating element 24 within the renal arteryas shown in FIG. 24G may improve the reliability and consistency of thetreatment. Since angiographic guidance such as fluoroscopy only providesvisualization in two dimensions, it is generally only possible in theanterior/posterior view to obtain visual confirmation of wall contact atthe superior (vertex) and inferior (bottom) of the renal artery. Foranterior and posterior treatments, it may be desirable to first obtainconfirmation of contact at a superior or inferior location and thenrotate the catheter such that the thermal heating element travelscircumferentially along the vessel wall until the desired treatmentlocation is reached. Physiologic data such as impedance can beconcurrently monitored to ensure that wall contact is maintained oroptimized during catheter rotation. Alternatively, the C-arm of thefluoroscope can be rotated to achieve a better angle for determiningwall contact.

FIG. 24 illustrate multiple longitudinally and circumferentially spacedfocal lesions that are created by repositioning thermal element 24through a combination of second flexure zone deflection, and elongatedshaft rotation and/or translation. In some of the previously describedembodiments of the treatment device, such multiple focal lesions may becreated with multiple thermal elements 24 positioned along the length ofthe distal end region 20. Additionally or alternatively, in some of thepreviously described embodiments of the treatment device, such multiplefocal lesions may be created by repositioning thermal element(s) 24solely through second flexure zone deflection in multiple planes, solelythrough elongated shaft translation, solely through elongated shaftrotation, or solely through any subset of second flexure zonedeflection, elongated shaft translation and elongated shaft rotation.

Another alternative treatment approach that reduces the amount ofrotation required is to create a first thermally affected tissue region98(a), for example as shown in FIG. 24D and instead of rotating theelongated shaft 16 as shown in FIG. 24E, the second flexure zone 34 canbe deflected in a second direction as shown in FIG. 25A to create asecond thermally affected tissue region 98(b). By combining translation,rotation and deflection of second flexure zone 34 in multiple directionsto manipulate the distal assembly 20 the caregiver can create severalthermally affected tissue regions 98(a), 98(b), 98(c) and 98(d) on thevessel wall as shown in FIGS. 25A to 25F

FIGS. 28A to 28C provide fluoroscopic images of a treatment device,similar to the one shown in FIG. 5 but without a second flexure zonecapable of multi-directional deflection, within a renal artery during ananimal study. FIG. 28A shows positioning of the treatment device andthermal heating element 24 at a distal treatment location. The secondflexure zone 34 has been deflected to position the thermal heatingelement 24 in contact with the vessel wall and to cause flexure in thethird flexure zone 44. FIG. 28A also shows contact region 124 where theapex of the bend of the second flexure zone 34 is in contact with thevessel wall in radial or angular opposition to contact between thethermal heating element and vessel wall. FIG. 28B shows the placement ofthe treatment device at a more proximal treatment location followingcircumferential rotation and axial retraction. FIG. 28C shows theplacement of the treatment device at a proximal treatment location justdistal to the junction of the aorta and renal artery. FIGS. 28D and 28Eprovide analogous fluoroscopic images depicting the treatment devicepositioned for treatment within a human renal artery. FIG. 28D shows thetreatment device, similar to the one shown in FIG. 5 but without asecond flexure zone capable of multi-directional deflection, advanced toa distal treatment location similar to that described above with respectto FIG. 28A. FIG. 28E shows the treatment device in a proximal treatmentposition similar to that described above with respect to FIG. 28C.

Experience using the treatment device of FIGS. 28A to 28E revealed thatthe treatment device preformed the desired functions of for (i)percutaneous introduction into a femoral, radial, or brachial arterythrough a small-diameter access site; (ii) atraumatic passage throughthe tortuous intravascular path through an iliac artery, into the aorta,and into a respective left/right renal artery, including (iii)accommodating significant flexure at the junction of the left/rightrenal arteries and aorta to gain entry into the respective left or rightrenal artery; (iv) accommodating controlled translation, deflection,and/or rotation within the respective renal artery to attain proximityto and a desired alignment with an interior wall of the respective renalartery; (v) allowing the placement of at least one energy deliveryelement into contact with tissue on the interior wall in an orientationthat optimizes the active surface area of the energy delivery element;and (vi) allowing substantially stable contact force between the atleast one energy delivery element and the interior wall during motion ofthe renal artery with respect to the aorta due to respiration and/orblood flow pulsatility.

However, experience using the treatment device of FIGS. 28A to 28E alsorevealed that the functions of (v), and (vi) could be improved bymodifying the treatment device to have a second flexure zone configuredfor multiple direction deflection as described in the presentapplication. In addition, a second flexure zone configured for multipledirection deflection is expected to reduce the need for rotation of thetreatment device within the renal artery by facilitating the ability toattain proximity to and a desired alignment with an interior wall of therespective renal artery, particularly when used in renal arteries withgreater degrees of tortuousity.

Since both the thermal heating element 24 and solder 130 at the distalend of the second flexure zone 34 can be radiopaque, as shown in FIGS.28A to 28C, the operator using angiographic visualization can use theimage corresponding to the first treatment location to relativelyposition the treatment device for the second treatment. For example, inrenal arteries of average length, it is desirable for the clinicaloperator to treat at about every 5 mm along the length of the mainartery. In embodiments where the length of the third flexure zone 44 is5 mm, the operator can simply retract the device such that the currentposition of the thermal heating element 24 is longitudinally alignedwith the position of the solder 130 in the previous treatment.

In another embodiment, a different type of radiopaque marker can replacesolder 130. For example, a band of platinum can be attached to thedistal end of the second flexure zone to serve as a radiopaque marker.

Since angiographic visualization of the vasculature generally requirescontrast agent to be infused into the renal artery, it may be desirableto incorporate within or alongside the treatment device a lumen and/orport for infusing contrast agent into the blood stream. Alternatively,the contrast agent can be delivered into the blood alongside thetreatment device within the annular space between the treatment deviceand the guide catheter through which the device is delivered.

Exposure to thermal energy (heat) in excess of a body temperature ofabout 37° C., but below a temperature of about 45° C., may inducethermal alteration via moderate heating of the target neural fibers orof vascular structures that perfuse the target fibers. In cases wherevascular structures are affected, the target neural fibers are deniedperfusion resulting in necrosis of the neural tissue. For example, thismay induce non-ablative thermal alteration in the fibers or structures.Exposure to heat above a temperature of about 45° C., or above about 60°C., may induce thermal alteration via substantial heating of the fibersor structures. For example, such higher temperatures may thermallyablate the target neural fibers or the vascular structures. In somepatients, it may be desirable to achieve temperatures that thermallyablate the target neural fibers or the vascular structures, but that areless than about 90° C., or less than about 85° C., or less than about80° C., and/or less than about 75° C. Regardless of the type of heatexposure utilized to induce the thermal neuromodulation, a reduction inrenal sympathetic nerve activity (“RSNA”) is expected.

C. Rotation Controller

As will be discussed later in greater detail, it is desirable to rotatethe device within the renal artery after the thermal heating element isin contact with the vessel wall. However, it may be cumbersome andawkward for a clinical practitioner to rotate the entire handle assemblyat the proximal end of the device, particularly given the dimensions ofthe renal anatomy. In one representative embodiment, as shown in FIGS.19A and 19B, the proximal end of the shaft 16 is coupled to the handleassembly 200 by a rotator 230.

The proximal end of the force transmitting section 30 is attached to astationary coupling 88 on the rotator 230. Rotation of the rotator 230(as FIG. 19A shows) thereby rotates the force transmitting section 30,and, with it, the entire elongated shaft 16, without rotation of thehandle assembly 200. As FIG. 19A shows, a caregiver is thereby able tohold the proximal portion of the handle assembly 200 rotationallystationary in one hand and, with the same or different hand, apply atorsional force to the rotator 230 to rotate the elongated shaft 16.This allows the actuator to remain easily accessed for controlleddeflection.

Since there are cables and wires running from the handle assemblythrough the shaft of the device (e.g., control 40, electricaltransmission wire and/or sensor/thermocouple wire(s) 29, etc.), it isdesirable to limit rotation of the shaft relative to these wires inorder to avoid unnecessary entanglement and twisting of these wires. Arotational limiting element can be incorporated into the handle assemblyand rotator to address this issue. The rotator 230 and handle assemblycan be configured to allow for the optimal number of revolutions for theshaft, given such structural or dimensional constraints (e.g., wires).The components of the handle assembly may be configured, for example toallow for a finite number of revolutions of the shaft (e.g., two)independent of the handle assembly. Limiting rotation of the shaft tothe optimal number of revolutions may be achieved by any number ofcommonly known mechanical features.

As has been described and will be described in greater detail later, byintravascular access, the caregiver can manipulate the handle assembly200 to locate the distal end region 20 of the elongated shaft 16 withinthe respective renal artery. The caregiver can then operate the actuator260 on the handle assembly 200 (see FIGS. 19A and 16B) to deflect thethermal heating element 24 about the second flexure zone 34. Thecaregiver can then operate the rotator 230 on the handle assembly 200(see FIGS. 19A and 19B) to apply a rotational force along the elongatedshaft 16. The rotation of the elongated shaft 16 when the second flexurezone 34 is deflected within the respective renal artery rotates thethermal heating element 24 within the respective renal artery, making iteasier to achieve contact with the vessel wall and determine whetherthere is wall contact, particularly in planes where there is poorangiographic visualization.

In an additional aspect of the disclosed technology, the handle assembly200 may be configured to minimize operator/caregiver handling of thedevice while it is within the patient. As shown, for example, in FIG.19B, the handle assembly also comprises one or more surfaces 243 thatsubstantially conform to the surface beneath (e.g., operating table).This surface 243, which is shown to be substantially flat in FIG. 19B,can alternatively be curved, shaped or angled depending on theconfiguration and/or geometry of the beneath surface. The conformingsurface 243 enables the clinical operator to keep the handle assembly200 stable when the treatment device 12 is within the patient. In orderto rotate the device when it is inside the patient, the operator cansimply dial the rotator 230 without any need to lift the handleassembly. When the operator desires to retract the device for subsequenttreatments, the operator can simply slide the handle assembly along thebeneath surface to the next position. Again, this mitigates the risk ofinjury due to operator error or over handling of the treatment device.Additionally or alternatively, the lower surface can engage the surfaceunderneath using clips, texture, adhesive, etc.

Additional enhancements to the rotation mechanism disclosed hereininclude providing tactile and/or visual feedback on the rotationalfitting so that the operator can exercise greater control and care inrotating the device. The rotator 230 can also be selectively locked tothe handle assembly, thereby preventing further rotation, if theoperator wishes to hold the treatment device in a particular angularposition. Another optional enhancement includes providing distancemarkers along the shaft/handle assembly to enable the operator to gaugedistance when retracting the treatment device.

D. Control of Applied Enemy

With the treatments disclosed herein for delivering therapy to targettissue, it may be beneficial for energy to be delivered to the targetneural structures in a controlled manner. The controlled delivery ofenergy will allow the zone of thermal treatment to extend into the renalfascia while reducing undesirable energy delivery or thermal effects tothe vessel wall. A controlled delivery of energy may also result in amore consistent, predictable and efficient overall treatment.Accordingly, the generator 26 desirably includes programmed instructionscomprising an algorithm 102 (see FIG. 5) for controlling the delivery ofpower and energy to the thermal heating device. The algorithm 102, arepresentative embodiment of which is shown in FIG. 26, can beimplemented as a conventional computer program for execution by aprocessor coupled to the generator 26. A caregiver using step-by-stepinstructions can also implement the algorithm 102 manually.

The operating parameters monitored in accordance with the algorithm mayinclude, for example, temperature, time, impedance, power, flowvelocity, volumetric flow rate, blood pressure, heart rate, etc.Discrete values in temperature may be used to trigger changes in poweror energy delivery. For example, high values in temperature (e.g. 85degrees C.) could indicate tissue desiccation in which case thealgorithm may decrease or stop the power and energy delivery to preventundesirable thermal effects to target or non-target tissue. Timeadditionally or alternatively may be used to prevent undesirable thermalalteration to non-target tissue. For each treatment, a set time (e.g., 2minutes) is checked to prevent indefinite delivery of power.

Impedance may be used to measure tissue changes. Impedance indicates theelectrical property of the treatment site. If a thermal inductive,electric field is applied to the treatment site the impedance willdecrease as the tissue cells become less resistive to current flow. Iftoo much energy is applied, tissue desiccation or coagulation may occurnear the electrode, which would increase the impedance as the cells losewater retention and/or the electrode surface area decreases (e.g., viathe accumulation of coagulum). Thus, an increase in tissue impedance maybe indicative or predictive of undesirable thermal alteration to targetor non-target tissue.

Additionally or alternatively, power is an effective parameter tomonitor in controlling the delivery of therapy. Power is a function ofvoltage and current. The algorithm may tailor the voltage and/or currentto achieve a desired power.

Derivatives of the aforementioned parameters (e.g., rates of change)also may be used to trigger changes in power or energy delivery. Forexample, the rate of change in temperature could be monitored such thatpower output is reduced in the event that a sudden rise in temperatureis detected. Likewise, the rate of change of impedance could bemonitored such that power output is reduced in the event that a suddenrise in impedance is detected.

As seen in FIG. 26, when a caregiver initiates treatment (e.g., via thefoot pedal), the algorithm 102 commands the generator 26 to graduallyadjust its power output to a first power level P₁ (e.g., 5 watts) over afirst time period t₁ (e.g., 15 seconds). The power increase during thefirst time period is generally linear. As a result, the generator 26increases its power output at a generally constant rate of P₁/t₁.Alternatively, the power increase can be non-linear (e.g., exponentialor parabolic) with a variable rate of increase. Once P₁ and t₁ areachieved, the algorithm can hold at P₁ until a new time t₂ for apredetermined period of time t₂−t₁ (e.g., 3 seconds). At t₂ power isincreased by a predetermined increment (e.g., 1 watt) to P₂ over apredetermined period of time, t₃−t₂ (e.g., 1 second). This power ramp inpredetermined increments of about 1 watt over predetermined periods oftime can continue until a maximum power P_(MAX) is achieved or someother condition is satisfied. In one embodiment, P_(MAX) is 8 watts. Inanother embodiment P_(MAX) is 10 watts. Optionally, the power may bemaintained at the maximum power P_(MAX) for a desired period of time orup to the desired total treatment time (e.g., up to about 120 seconds).

In FIG. 26, algorithm 102 illustratively comprises a power-controlalgorithm. However, it should be understood that algorithm 102alternatively may comprise a temperature-control algorithm. For example,power may be gradually increased until a desired temperature (ortemperatures) is obtained for a desired duration (durations). In anotherembodiment, a combination power-control and temperature-controlalgorithm may be provided.

As discussed, the algorithm 102 includes monitoring certain operatingparameters (e.g., temperature, time, impedance, power, flow velocity,volumetric flow rate, blood pressure, heart rate, etc.). The operatingparameters can be monitored continuously or periodically. The algorithm102 checks the monitored parameters against predetermined parameterprofiles to determine whether the parameters individually or incombination fall within the ranges set by the predetermined parameterprofiles. If the monitored parameters fall within the ranges set by thepredetermined parameter profiles, then treatment can continue at thecommanded power output. If monitored parameters fall outside the rangesset by the predetermined parameter profiles, the algorithm 102 adjuststhe commanded power output accordingly. For example, if a targettemperature (e.g., 65 degrees C.) is achieved, then power delivery iskept constant until the total treatment time (e.g., 120 seconds) hasexpired. If a first temperature threshold (e.g., 70 degrees C.) isachieved or exceeded, then power is reduced in predetermined increments(e.g., 0.5 watts, 1.0 watts, etc.) until a target temperature isachieved. If a second power threshold (e.g., 85 degrees C.) is achievedor exceeded, thereby indicating an undesirable condition, then powerdelivery can be terminated. The system can be equipped with variousaudible and visual alarms to alert the operator of certain conditions.

The following is a non-exhaustive list of events under which algorithm102 may adjust and/or terminate/discontinue the commanded power output:

-   -   (1) The measured temperature exceeds a maximum temperature        threshold (e.g., about 70 degrees to about 85 degrees C.).    -   (2) The average temperature derived from the measured        temperature exceeds an average temperature threshold (e.g.,        about 65 degrees C.).    -   (3) The rate of change of the measured temperature exceeds a        rate of change threshold.    -   (4) The temperature rise over a period of time is below a        minimum temperature change threshold while the generator 26 has        non-zero output. Poor contact between the thermal heating        element 24 and the arterial wall can cause such a condition.    -   (5) A measured impedance exceeds an impedance threshold (e.g.,        <20 Ohms, or >500 Ohms).    -   (6) A measured impedance exceeds a relative threshold (e.g.,        impedance decreases from a starting or baseline value and then        rises above this baseline value)    -   (7) A measured power exceeds a power threshold (e.g., >8 Watts        or >10 Watts).    -   (8) A measured duration of power delivery exceeds a time        threshold (e.g., >120 seconds).

E. Control of Active Cooling and Applied Energy

With the treatments disclosed herein for delivering therapy to targettissue, it may be beneficial to actively cool the thermal heatingelement and/or non-target tissue in the vicinity of the thermal heatingelement. For example, infusate, such as a thermal fluid (e.g., roomtemperature or chilled saline), may be injected (open circuit system)into the patient's blood stream in the vicinity of the treatment siteduring power or energy delivery to act as a conductive and/or convectiveheat sink that removes thermal energy (see, e.g., FIG. 9C). Infusateinjection (e.g., continuous infusate injection) may provide more—or morerapid—heat transfer, as well as more uniform and/or predictable heattransfer dynamics, as compared to the passive cooling provided bypulsatile blood flow (see, e.g., FIGS. 9A and 9B). Infusate injectionalso may remove blood proteins from the thermal heating element, therebyreducing a risk of coagulum formation. In addition or as an alternativeto infusate injection, active cooling may comprise a closed circuitsystem with a circulating or stationary coolant (e.g., a cryogenicfluid, chilled saline, etc.) that removes heat from the thermal heatingelement, and indirectly from non-target tissue, during power or energydelivery.

Energy is defined as Power×Time. When closed or open circuit activecooling is provided, if the power and time over which energy isdelivered are not altered as compared to when active cooling is notprovided, then the energy delivered also is not altered. Thus, theactive cooling may further protect non-target tissue at the vessel wallfrom injury, e.g., may lower the surface temperature of the vessel wallduring power delivery.

If, however, active cooling is provided in combination with increasedpower but consistent duration of power delivery, the energy delivered isincreased, which may facilitate the safe creation of a deeper or largerlesion than would be feasible without active cooling that protectsnon-target tissue at the vessel wall. Likewise, providing active coolingin combination with increased duration of power delivery but consistentmagnitude of power level would increase the energy delivered, againpotentially facilitating the safe creation of a deeper or larger lesionthan would be feasible absent active cooling.

Active cooling also may facilitate delivery of energy via an increasedpower level in combination with decreased power delivery duration. Thismay facilitate more rapid lesion creation, which could shorten thetreatment time. Depending on the relative magnitudes of power magnitudeincrease and power duration decrease, it also may facilitate thedelivery of more energy in less time, which may facilitate the safecreation of a deeper or larger lesion in less time.

When active cooling is achieved via an open circuit system utilizingintravascular infusate (e.g., saline) infusion, the volume and rate ofinfusate infusion are of note. Intravascular infusate infusion may, forexample, be provided in the vicinity of a treatment site from betweenabout 0-10 seconds (e.g., about 5 seconds) prior to power delivery, thenduring power delivery, and for about 0-10 seconds (e.g., about 5seconds) after power delivery. In some patients, intravascular infusionof a significant saline volume may induce pulmonary edema or heartfailure, and some patient groups may be at higher risk of suchcomplications. These higher risk patient groups may include patientgroups that are therapeutically indicated for renal neuromodulation,including, for example, those with a history of heart failure or heartdisease, renal insufficiency and/or diabetes mellitus.

Advantageously, the magnitude of maximum power delivered during renalneuromodulation treatment in accordance with the present invention maybe relatively low (e.g., less than about 15 Watts, for example, lessthan about 10 Watts or less than about 8 Watts) as compared, forexample, to the power levels utilized in electrophysiology treatments toachieve cardiac tissue ablation (e.g., power levels greater than about15 Watts, for example, greater than about 30 Watts). Since relativelylow power levels may be utilized to achieve such renal neuromodulation,the flow rate and/or total volume of intravascular infusate injectionneeded to maintain the thermal heating element and/or non-target tissueat or below a desired temperature during power delivery (e.g., at orbelow about 50° C., for example, at or below about 45° C.) also may berelatively lower than would be required at the higher power levels used,for example, in electrophysiology treatments (e.g., power levels aboveabout 15 Watts). This relative reduction in flow rate and/or totalvolume of intravascular infusate infusion advantageously may facilitatethe use of intravascular infusate in higher risk patient groups thatwould be contraindicated were higher power levels and, thus,correspondingly higher infusate rates/volumes utilized (e.g., patientswith heart disease, heart failure, renal insufficiency and/or diabetesmellitus).

When the intravascular infusate comprises saline, one liter of thesaline may comprise about 9 grams of sodium chloride, which includesabout 3.6 grams of sodium. 3.6 grams of sodium is about 150% of therecommended daily allowance for patients with heart failure orhypertension. Each liter of saline also may contain about 1,000 Units ofthe anti-coagulant heparin. Furthermore, saline injection increasesvenous pressure, and thereby capillary pressure, which increases theamount of fluid leaving the vasculature. If lymphatic drainage and renalexcretion (urine output) are not able to maintain homeostasis, fluidaccumulates and may cause pulmonary edema or heart failure.

Based on the foregoing, it may be desirable to limit saline (e.g., roomtemperature saline) infusion to less than about 1 Liter, for example,less than about 500 mL, less than about 250 mL or less than about 100mL. Such limitation of saline infusion volume may facilitate infusion inhigher risk patient groups, for example, those with heart disease, heartfailure, diabetes mellitus and/or renal insufficiency. When the maximumpower level does not exceed about 15 Watts, e.g., does not exceed about10 Watts, it is expected that an infusion rate less than or equal toabout 15 mL/minute, e.g., less than or equal to about 10 mL/minute,would be sufficient to maintain the thermal heating element at or belowa desired temperature, e.g., at or below about 50° C., for example, ator below about 45° C. For treatment times of two minutes or less, theseinfusion rates facilitate treatment at multiple sites while maintaininga total infusion volume below about 1 Liter, 500 mL, 250 mL and/or 100mL. A control algorithm, such as algorithm 102 or a manual controller,may be provided to control the infusion rate and/or total infusionvolume, while a fluid pump may be provided to propel the infusatethrough the elongated shaft 16 at the desired (e.g., controlled) rate.Optionally, the infusate infusion rate may be increased as power isincreased, which may further reduce the total infusion volume ascompared to providing a consistent infusion rate tailored to the maximumpower level delivered.

As an example, were saline to be injected for 5 seconds pre- andpost-treatment, as well as during 2 minutes of treatment (i.e., weresaline to be injected for about 130 seconds per treatment site), eachtreatment at an infusion rate of 15 mL/minute would result in a totalinfusion volume of about 32.5 mL. Thus, treatment may be performed atabout 3 treatment sites while maintaining a total infusion volume belowabout 100 mL, at over 7 treatment sites while maintaining a totalinfusion volume below about 250 mL, at about 15 treatment sites whilemaintaining a total infusion volume below about 500 mL, and at over 30treatment sites while maintaining a total infusion volume below about 1Liter. Treatments of less than 2 minutes may facilitate total infusionvolumes that are even lower for a given number of treatment sites and/ormay facilitate treatment at more sites while maintaining total infusionvolume below a desired threshold.

Likewise, were saline to be injected for 5 seconds pre- andpost-treatment, as well as during 2 minutes of treatment (i.e., weresaline to be injected for about 130 seconds per treatment site), eachtreatment at an infusion rate of 10 mL/minute would result in a totalinfusion volume of about 21.7 mL. Thus, treatment may be performed atover 4 treatment sites while maintaining a total infusion volume belowabout 100 mL, at over 11 treatment sites while maintaining a totalinfusion volume below about 250 mL, at about 23 treatment sites whilemaintaining a total infusion volume below about 500 mL, and at about 46treatment sites while maintaining a total infusion volume below about 1Liter. Treatments of less than 2 minutes may facilitate total infusionvolumes that are even lower for a given number of treatment sites(and/or may facilitate treatment at more sites while maintaining totalinfusion volume below a desired threshold).

V. PREPACKAGED KIT FOR DISTRIBUTION, TRANSPORT AND SALE OF THE DISCLOSEDAPPARATUSES AND SYSTEMS

As shown in FIG. 27, one or more components of the system 10 shown inFIG. 5 can be packaged together for convenient delivery to and use bythe customer/clinical operator. Components suitable for packaginginclude, the treatment device 12, the cable 28 for connecting thetreatment device 12 to the generator 26, the neutral or dispersiveelectrode 38, and one or more guide catheters 94 (e.g., a renal guidecatheter). Cable 28 can also be integrated into the treatment device 12such that both components are packaged together. Each component may haveits own sterile packaging (for components requiring sterilization) orthe components may have dedicated sterilized compartments within the kitpackaging. This kit may also include step-by-step instructions for use126 that provide the operator with technical product features andoperating instructions for using the system 10 and treatment device 12,including all methods of insertion, delivery, placement and use of thetreatment device disclosed herein.

VI. ADDITIONAL CLINICAL USES OF THE DISCLOSED APPARATUSES, METHODS ANDSYSTEMS

Although much of the disclosure in this Specification relates to atleast partially denervating a kidney of a patient to block afferentand/or efferent neural communication from within a renal blood vessel(e.g., renal artery), the apparatuses, methods and systems describedherein may also be used for other intravascular treatments. For example,the aforementioned catheter system, or select aspects of such system,can be placed in other peripheral blood vessels to deliver energy and/orelectric fields to achieve a neuromodulatory affect by altering nervesproximate to these other peripheral blood vessels. There are a number ofarterial vessels arising from the aorta which travel alongside a richcollection of nerves to target organs. Utilizing the arteries to accessand modulate these nerves may have clear therapeutic potential in anumber of disease states. Some examples include the nerves encirclingthe celiac trunk, superior mesenteric artery, and inferior mesentericartery.

Sympathetic nerves proximate to or encircling the arterial blood vesselknown as the celiac trunk may pass through the celiac ganglion andfollow branches of the celiac trunk to innervate the stomach, smallintestine, abdominal blood vessels, liver, bile ducts, gallbladder,pancreas, adrenal glands, and kidneys. Modulating these nerves either inwhole (or in part via selective modulation) may enable treatment ofconditions including (but not limited to) diabetes, pancreatitis,obesity, hypertension, obesity related hypertension, hepatitis,hepatorenal syndrome, gastric ulcers, gastric motility disorders,irritable bowel syndrome, and autoimmune disorders such as Chron'sdisease.

Sympathetic nerves proximate to or encircling the arterial blood vesselknown as the inferior mesenteric artery may pass through the inferiormesenteric ganglion and follow branches of the inferior mesentericartery to innervate the colon, rectum, bladder, sex organs, and externalgenitalia. Modulating these nerves either in whole (or in part viaselective modulation) may enable treatment of conditions including (butnot limited to) GI motility disorders, colitis, urinary retention,hyperactive bladder, incontinence, infertility, polycystic ovariansyndrome, premature ejaculation, erectile dysfunction, dyspareunia, andvaginismus.

While arterial access and treatments have received attention in thisSpecification, the disclosed apparatuses, methods and systems can alsobe used to deliver treatment from within a peripheral vein or lymphaticvessel.

VII. CONCLUSION

The above detailed descriptions of embodiments of the invention are notintended to be exhaustive or to limit the invention to the precise formdisclosed above. Although specific embodiments of, and examples for, theinvention are described above for illustrative purposes, variousequivalent modifications are possible within the scope of the invention,as those skilled in the relevant art will recognize. For example, whilesteps are presented in a given order, alternative embodiments mayperform steps in a different order. The various embodiments describedherein can also be combined to provide further embodiments.

From the foregoing, it will be appreciated that specific embodiments ofthe invention have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the invention. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.For example, much of the disclosure herein describes a thermal heatingelement 24 or electrode 46 in the singular. It should be understood thatthis application does not exclude two or more thermal heating elementsor electrodes

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A multi-directional deflectable catheter apparatus for thermallymodulating renal nerves from within a renal artery of a patient, thecatheter apparatus comprising: an elongated tubular shaft extendingalong an axis, the elongated tubular shaft having a proximal end and adistal end; a handle proximal to the proximal end of the elongatedtubular shaft; a flexible tubular structure distal from the distal endof the elongated tubular shaft, the flexible tubular structure adaptedto make a transitional bend from the aorta of the patient to the renalartery; a multi-directional deflectable assembly distal from theflexible tubular structure; a flexure control element coupled to themulti-directional deflectable assembly; a flexure controller carried bythe handle and coupled to the flexure control element, the flexurecontroller adapted to apply a force via the flexure control element tothe multi-directional deflectable assembly; and a thermal elementcarried by or distal from the multi-directional deflectable assembly;wherein the multi-directional deflectable assembly is adapted forflexure in at least two radial directions in a common plane through theaxis of the elongated tubular shaft upon application of force via theflexure control element; wherein the multi-directional deflectableassembly is adapted upon flexure to position the thermal element incontact with an inner wall of the renal artery.
 2. The catheterapparatus of claim 1 wherein the multi-directional deflectable assemblycomprises a centrally-positioned spine.
 3. The catheter apparatus ofclaim 2 wherein the centrally-positioned spine comprises a spinalflexure element.
 4. The catheter apparatus of claim 3 wherein the spinalflexure element comprises a ribbon, and wherein the flexure controlelement comprises a first control wire coupled to the multi-directionaldeflectable assembly on a first side of the ribbon and a second controlwire coupled to the multi-directional deflectable assembly on a secondside of the ribbon.
 5. The catheter apparatus of claim 4 wherein theribbon is configured for flexure towards the first control wire inresponse to tension applied by the first control wire and towards thesecond control wire in response to tension applied by the second controlwire.
 6. The catheter apparatus of claim 2 wherein thecentrally-positioned spine comprises a first spinal flexure element anda second spinal flexure element, each spinal flexure element adapted forbi-directional movement.
 7. The catheter apparatus of claim 6 whereinthe first spinal flexure element is angularly offset from the secondspinal flexure element about the axis of the elongated tubular shaft. 8.The catheter apparatus of claim 1 wherein the multi-directionaldeflectable assembly has a length from about 5 mm to about 15 mm.
 9. Thecatheter apparatus of claim 1 wherein the thermal element is configuredto apply thermal treatment using at least one of radiofrequency energy,cooled radiofrequency energy, microwave energy, ultrasound energy,laser/light energy, thermal fluid, resistive heating, and cryogenicfluid.
 10. The catheter apparatus of claim 1 wherein the thermal elementcomprises a single electrode.
 11. The catheter apparatus of claim 1wherein the thermal element comprises multiple electrodes.
 12. Thecatheter apparatus of claim 1 wherein the multi-directional deflectableassembly is configured for a state of maximum flexure, and wherein thestate of maximum flexure is achieved when the multi-directionaldeflectable assembly comprises a transitional bend having a radius ofcurvature.
 13. The catheter apparatus of claim 12 wherein the radius ofcurvature is no greater than about 25 mm.
 14. The catheter apparatus ofclaim 1 wherein the flexible tubular structure is more flexible than theelongated tubular shaft, and wherein the multi-directional deflectableassembly is more flexible than the flexible tubular structure.
 15. Thecatheter apparatus of claim 14 wherein the elongated tubular shaft, theflexible tubular structure and the multi-directional deflectableassembly comprise a single piece tubular structure.
 16. The catheterapparatus of claim 15 wherein the increased flexibility of the flexibletubular structure and the multi-directional deflectable assembly resultfrom laser cutting of the single piece tubular structure.
 17. Thecatheter apparatus of claim 1 wherein the thermal element is configuredto create a thermal lesion comprising at least 30% circumferentialcoverage of the renal artery wall.
 18. The catheter apparatus of claim 1wherein the elongated tubular shaft, the multi-directional deflectableassembly and the thermal element are sized and configured forintravascular delivery into the renal artery via a 6 French guidecatheter.
 19. The catheter apparatus of claim 1, further comprising asensor adjacent to, on, or within the thermal element, the sensorconfigured to monitor a parameter of at least one of the apparatus andthe renal artery wall.
 20. The catheter apparatus of claim 19 whereinthe sensor comprises at least one of a temperature sensor, impedancesensor, optical sensor, force sensor, strain sensor or micro sensor.21-47. (canceled)